Pancreatic Ductal Adenocarcinoma

MONDO:0005184 Pathograph 55 Show in embeddings browser pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a malignant pancreatic epithelial neoplasm with ductal differentiation. Most tumors harbor an activating KRAS mutation together with alterations in tumor-suppressor pathways, but KRAS-wild-type tumors include distinct actionable drivers. Acinar reprogramming, ductal-origin models and several precursor lesions contribute to current initiation models; ductal morphology does not establish a unique human cell of origin. Desmoplastic fibroblast states, myeloid and lymphoid suppression, altered antigen presentation, nutrient scavenging and metabolic adaptation shape invasion and treatment response. Resectability and metastatic extent determine clinical management. Surgery with systemic therapy offers potential long-term control in selected localized disease; advanced disease is treated with systemic regimens and, in defined molecular subsets, targeted or immune therapies. Daraxonrasib has randomized clinical efficacy in previously treated metastatic PDAC. Its resistance mechanisms now have paired clinical ctDNA evidence, whereas immune-remodeling/checkpoint combinations remain preclinical.

Ask OpenScientist

Ask a research question about Pancreatic Ductal Adenocarcinoma. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

🏷

Classifications

ICD-O Morphology

Harrison's Part

🔗

Mappings

MONDO

MONDO:0005184 pancreatic ductal adenocarcinoma

MONDO provides an exact disease term for pancreatic ductal adenocarcinoma.

NCIT

NCIT:C9120 Pancreatic Ductal Adenocarcinoma

NCIT provides an exact neoplasm term for pancreatic ductal adenocarcinoma.

NCIT

NCIT:C9120 Pancreatic Ductal Adenocarcinoma

NCIT provides an exact neoplasm term for pancreatic ductal adenocarcinoma.

◆

Subtypes

Classical Subtype

An expression program enriched for epithelial differentiation. Classical and basal-like states can coexist within a tumor; bulk-expression assignments do not imply immutable, mutually exclusive diseases. The original virtual-microdissection cohorts associated classical tumors with better survival than basal-like tumors.

Show evidence (1 reference)

PMID:26343385 SUPPORT Computational

"we have identified and validated two tumor subtypes, including a 'basal-like' subtype that has worse outcome and is molecularly similar to basal tumors in bladder and breast cancers."

Moffitt et al. used virtual microdissection of gene expression data to identify classical and basal-like subtypes of PDAC, with classical having better prognosis.

Basal-like Subtype

A basal/squamous expression program associated with adverse outcome in the original profiling cohorts. State abundance and plasticity vary within tumors and under treatment. In autochthonous mouse PDAC, basal-state ablation or basal-cell GM-CSF loss disrupted an immunosuppressive circuit and reduced tumors; this is not yet a validated human state-selective treatment.

Show evidence (2 references)

PMID:26343385 SUPPORT Computational

"patients with basal-like subtype tumors had an overall worse median survival of 11 months and 44% 1-year survival compared to 19 months and 70% 1-year survival for those with classical subtype tumors"

Moffitt et al. demonstrated basal-like subtype has significantly worse survival compared to classical subtype in PDAC.

PMID:42523238 SUPPORT Model Organism

"Knockout of a single cytokine, GM-CSF, specifically in basal cells recapitulated macrophage repolarization and lymphocyte recruitment observed upon basal state ablation and shrank tumors."

Basal-cell-specific genetic perturbation establishes an immune-organizing GM-CSF role in mouse PDAC. Human prognostic association does not establish the same intervention effect.

Comorbidities

Chronic Pancreatitis <-> Pancreatic Ductal Adenocarcinoma

◈

Mechanistic Hypotheses

RAS(ON) Inhibition Remodels the Immunosuppressive Microenvironment

ras_on_inhibition_immune_tme_remodeling EMERGING

Evidence balance 2 support

RAS(ON) multiselective inhibition directly remodels PDAC immunity in mouse models, including increased tumor MHC-I, altered myeloid states and T-cell/cDC-dependent responses. Checkpoint cotreatment can deepen control, but optimal partners, Treg behavior and durability vary by model. Neither universal Treg relief nor clinical daraxonrasib-checkpoint benefit is established. Autophagy and FAK are complementary antigen-presentation regulators rather than mutually exclusive alternatives.

Both July OpenScientist reports and their updated assessments now sit under kb/hypotheses/Pancreatic_Ductal_Adenocarcinoma after consolidation into this disease. PMID40057911 was already available when the immune report omitted it; the August 2026 CTLA-4/Treg study is subsequent evidence.

Pathograph links

Myeloid Suppression Relief and CD8 Effector Infiltration -> Immunosuppressive TME Reversibility under RAS(ON) Inhibition INDIRECT UNKNOWN INTERMEDIATES The observed treatment-induced change contributes to immune recognition or immune-dependent tumor control in the specified model.

Tumor-Cell FAS Induction and CD8-Mediated Killing -> Immunosuppressive TME Reversibility under RAS(ON) Inhibition INDIRECT UNKNOWN INTERMEDIATES The observed treatment-induced change contributes to immune recognition or immune-dependent tumor control in the specified model.

Antigen Presentation Restoration -> Immunosuppressive TME Reversibility under RAS(ON) Inhibition INDIRECT UNKNOWN INTERMEDIATES The observed treatment-induced change contributes to immune recognition or immune-dependent tumor control in the specified model.

USP20 Cholesterol-Metabolism CD8 Exhaustion Checkpoint -> Immune Evasion INDIRECT UNKNOWN INTERMEDIATES Cholesterol-associated dysfunction contributes to CD8 exhaustion.

USP20 Cholesterol-Metabolism CD8 Exhaustion Checkpoint -> Autophagy-Lysosome Growth Support INDIRECT KNOWN INTERMEDIATES USP20 stabilizes ULK1 and supports compensatory autophagy under KRAS-G12D or cholesterol inhibition. Intermediates: ULK1 stabilization

CDK8-CXCL2 Adaptive Immune Reversal -> Immune Evasion INDIRECT KNOWN INTERMEDIATES Under prolonged MRTX1133 exposure, CXCL2 and FAS changes restore immune suppression. Intermediates: CXCL2 secretion; Reduced FAS-mediated susceptibility to immune killing

IL6-CAF and Myeloid Rebound after SOS1-MEK Inhibition -> Immune Evasion INDIRECT UNKNOWN INTERMEDIATES Stromal and myeloid adaptation can limit the benefit of initial T-cell entry.

Adaptive CD24 Antiphagocytic Signaling -> Immune Evasion INDIRECT KNOWN INTERMEDIATES Induced CD24 reduces macrophage-mediated tumor-cell clearance in selective-KRAS-inhibitor models.

Deep research

OpenScientist citations 13 citations 2026-07-24T01:13:35.827549

Show evidence (2 references)

PMID:40057911 SUPPORT Model Organism

"In this study, we report that RAS(ON) multi-selective inhibition led to rapid and profound PDAC regressions in immunocompetent mice, decreasing myeloid cells and increasing T cells and macrophages in the tumor microenvironment."

Direct PDAC evidence was omitted from the immune report despite being cited in the resistance report.

PMID:40057911 SUPPORT Model Organism

"The depth and duration of tumor regression depended on T cells and conventional dendritic cells."

Depletion/genetic experiments establish immune contribution in mouse PDAC.

Acquired Resistance to RAS(ON) Multiselective Inhibition

ras_on_inhibitor_acquired_resistance EMERGING

Evidence balance 2 support

Daraxonrasib resistance includes clinical KRAS amplification and other RAS-pathway alterations, with mutant-allele assignment inferred by an exploratory variant-allele-frequency method. Preclinical and limited clinical findings support RTK bypass, MYC-related programs and allele-specific cyclophilin-A or EGFR/wild-type-RAS routes. The 44-patient paired ctDNA study updates the July report: patient mechanisms are no longer wholly unknown, but selected-cohort frequencies, non-genomic routes, pre-existing versus newly selected clones and optimal salvage remain unresolved. Distinct inhibitor classes and combination regimens must be kept explicit.

Pathograph links

Cyclophilin A Loss and Reduced Tri-Complex Engagement -> Acquired RAS(ON) Inhibitor Resistance INDIRECT UNKNOWN INTERMEDIATES Under the specified RAS-inhibitor exposure, this route can sustain tumor growth or reduce target inhibition. Source and regimen restrictions apply.

RAS-Independent Cell-Cycle Uncoupling -> Acquired RAS(ON) Inhibitor Resistance INDIRECT UNKNOWN INTERMEDIATES Under the specified RAS-inhibitor exposure, this route can sustain tumor growth or reduce target inhibition. Source and regimen restrictions apply.

On-Target RAS Reactivation and KRAS Amplification -> Acquired RAS(ON) Inhibitor Resistance INDIRECT UNKNOWN INTERMEDIATES Under the specified RAS-inhibitor exposure, this route can sustain tumor growth or reduce target inhibition. Source and regimen restrictions apply.

RTK and Feedback Pathway Reactivation -> Acquired RAS(ON) Inhibitor Resistance INDIRECT UNKNOWN INTERMEDIATES Under the specified RAS-inhibitor exposure, this route can sustain tumor growth or reduce target inhibition. Source and regimen restrictions apply.

Adaptive mTOR and JUN-AP1 Transcriptional Program -> Acquired RAS(ON) Inhibitor Resistance INDIRECT UNKNOWN INTERMEDIATES Under the specified RAS-inhibitor exposure, this route can sustain tumor growth or reduce target inhibition. Source and regimen restrictions apply.

MYC Amplification-Driven RAS-Independent Proliferation -> Acquired RAS(ON) Inhibitor Resistance INDIRECT UNKNOWN INTERMEDIATES Under the specified RAS-inhibitor exposure, this route can sustain tumor growth or reduce target inhibition. Source and regimen restrictions apply.

Adaptive CD24 Antiphagocytic Signaling -> Immune Evasion INDIRECT KNOWN INTERMEDIATES Induced CD24 reduces macrophage-mediated tumor-cell clearance in selective-KRAS-inhibitor models.

Deep research

OpenScientist citations 16 citations 2026-07-24T01:28:18.090810

Show evidence (2 references)

PMID:42581230 SUPPORT Human Clinical

"Here we report mechanisms of acquired resistance to daraxonrasib monotherapy observed through targeted sequencing of over 800 genes in paired pretreatment and end of treatment circulating tumor DNA samples from 44 patients in the phase 1/2 clinical trial."

August 2026 paired clinical sequencing supersedes the July reports and earlier assessment claim that no longitudinal clinical characterization was available.

PMID:42581230 SUPPORT Human Clinical

"Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26 of 44; 59%) of these patients, including, most notably, mutant KRAS amplifications in one-third (16 of 44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4 of 44; 9%), MAPK..."

Frequencies apply to 44 profiled patients with prior disease control followed by progression, not all treated PDAC patients; categories overlap. Mutant-allele attribution from ctDNA is exploratory and unconfirmed, as specified in Supplementary Table 3.

Discussions and Knowledge Gaps

Which cancer-associated fibroblast programs actively cause T-cell exclusion and checkpoint resistance in PDAC, and which stromal programs are tumor-restraining or merely correlative with desmoplastic burden?

KNOWLEDGE GAP OPEN gap_pdac_caf_program_t_cell_exclusion

Attached to

pathophysiology#Desmoplastic Stroma pathophysiology#CAF-Mediated T Cell Exclusion pathophysiology#Immune Evasion

PDAC desmoplasia is not a single therapeutic target: some CAF states may exclude effector T cells, whereas others may restrain invasion. A patient-derived organ-on-chip experiment can test whether specific CAF programs are causal for immune exclusion and whether reprogramming them improves T-cell cytotoxicity without removing tumor-restraining stroma.

Proposed experiments

Patient-derived PDAC organ-on-chip CAF reprogramming and T-cell infiltration assay

patient-derived organ-on-chip immunotherapy perturbation experiment

exp_pdac_patient_ooc_caf_t_cell_exclusion

Assemble a patient-derived PDAC organoid organ-on-chip with fibroblasts, endothelium, and immune cells; induce or suppress CAF programs including interferon-response CAF states; then measure T-cell infiltration, cytotoxicity, tumor viability, and stromal remodeling under checkpoint blockade.

Model systems

Patient-derived PDAC tumor-microenvironment organ-on-chip

Microfluidic human PDAC model combining patient-derived tumor organoids with fibroblasts, endothelial cells, and immune cells so stromal crosstalk, T-cell migration, and drug response can be measured in a standardized ex vivo platform.

ORGAN ON CHIP namo:OrganOnChip link

human NCBITaxon:9606

pancreas UBERON:0001264

pancreatic ductal cell CL:0002079 fibroblast CL:0000057 endothelial cell CL:0000115 T cell CL:0000084

Perturbations

CAF subtype induction and depletion

pathophysiology#Desmoplastic Stroma

Induce, suppress, or selectively deplete CAF states to separate immune-excluding and tumor-restraining stromal programs.

FAP

extracellular matrix organization GO:0030198

STING-driven interferon-response CAF induction

pathophysiology#CAF-Mediated T Cell Exclusion

STING agonism or matched interferon-response induction used to test whether an interferon-response CAF state decreases invasion and improves antitumor immune activity.

type I interferon signaling pathway GO:0060337

Immune checkpoint blockade

pathophysiology#Immune Evasion

Anti-PD-1/PD-L1 or matched checkpoint blockade applied with CAF perturbation to test whether stromal reprogramming is required for T-cell cytotoxicity.

immunotherapy NCIT:C15262

Readouts

T-cell infiltration and cytotoxicity

pathophysiology#CAF-Mediated T Cell Exclusion

Spatial T-cell entry into tumor organoid regions, activation markers, and tumor-cell killing after CAF-state perturbation.

T cell activation GO:0042110

high-content live imaging cytotoxicity assay

Direction: NEGATIVE

CAF-state trajectory

pathophysiology#Desmoplastic Stroma

Single-cell and spatial profiling of inflammatory, myofibroblastic, and interferon-response CAF programs after stromal perturbation.

single-cell transcriptomic profiling spatial transcriptomic profiling

Direction: POSITIVE

Tumor organoid viability under checkpoint blockade

pathophysiology#Immune Evasion

Tumor-cell survival after combined CAF perturbation and checkpoint blockade.

cell viability assay

Direction: NEGATIVE

Controls

Tumor organoid without CAF compartment

Patient-derived PDAC organoid chip lacking fibroblasts.

CAF-intact chip without T cells

Stromal chip lacking effector T cells to distinguish direct stromal effects from immune-mediated killing.

Isotype-control checkpoint antibody

Matched antibody control for checkpoint blockade.

Decision criterion

A causal CAF immune-exclusion program is supported if its induction reduces T-cell entry or killing and its suppression restores checkpoint response. A tumor-restraining CAF state is supported if induction lowers invasion or viability while preserving or improving T-cell function.

Would support

pathophysiology#CAF-Mediated T Cell Exclusion pathophysiology#Immune Evasion

Would refute

pathophysiology#CAF-Mediated T Cell Exclusion

Show evidence (3 references)

PMID:41610338 SUPPORT In Vitro

"incorporating PDOs with key components of the TME (fibroblasts, endothelial cells, and immune cells) within a microfluidic system"

Provides the recent patient-derived organ-on-chip precedent for a PDAC tumor-microenvironment experiment with stromal and immune compartments.

PMID:41610338 SUPPORT In Vitro

"model and assess the efficacy of immune checkpoint blockade for T cell cytotoxicity in PDAC"

Supports using this platform to adjudicate checkpoint response in the presence of patient-derived stromal context.

+ 1 more reference

⚙

Pathophysiology

Chronic Pancreatic Inflammation

Inflammation and tissue injury can cooperate with oncogenic KRAS to enable acinar reprogramming and precursor formation. In one adult acinar/centroacinar KRAS-G12V mouse model, chronic pancreatitis was necessary for tumor induction. This is a model-specific requirement, not a claim that every human PDAC requires clinically recognized pancreatitis. Human chronic pancreatitis is a strong risk factor with risk estimates dependent on follow-up and case definition.

macrophage CL:0000235 pancreatic stellate cell CL:0002410

inflammatory response GO:0006954 ↑ INCREASED

pancreas UBERON:0001264

Downstream

Acinar-to-Ductal Metaplasia Injury promotes ductal reprogramming in permissive pancreatic cells.

Early Dissemination and EMT Pancreatitis increased circulating pancreatic cells and EMT-associated dissemination in lineage-traced mice.

Show evidence (2 references)

PMID:17349585 SUPPORT Model Organism

"These observations suggest that, during adulthood, PDA stems from a combination of genetic (e.g., somatic K-Ras mutations) and nongenetic (e.g., tissue damage) events."

States the two-component model directly: the genetic lesion is modeled by the KRAS node and the nongenetic tissue-damage component is what this node is for.

PMID:35142721 SUPPORT Human Clinical

"There is an increased risk of PDAC in patients with CP, and incidence rates increase with CP disease duration."

The human counterpart of the mouse result, with risk rising as the inflammation persists. PARTIAL because it measures cancer incidence in inflamed pancreata rather than anything at this node itself.

Acinar-to-Ductal Metaplasia

Acinar cells can lose differentiated identity and adopt ductal-like programs during injury and KRAS-driven transformation. ADM is reversible in regenerative settings and is not synonymous with cancer. Persistent oncogenic signaling can channel reprogrammed cells into PanIN. Adult ductal cells can also initiate PDAC with cooperating p53 alterations in mice; the relative contribution of these origins in humans remains unresolved.

pancreatic acinar cell CL:0002064 pancreatic ductal cell CL:0002079

transdifferentiation GO:0060290 ↑ INCREASED

Downstream

Pancreatic Precursor Progression and Invasive Growth Persistent reprogramming can precede PanIN and invasive progression in an oncogenic context; regenerative ADM alone is insufficient.

Show evidence (3 references)

PMID:35176433 SUPPORT Other

"Acinar to ductal metaplasia (ADM) is the predominant form of ductal metaplasia in pancreas."

Establishes ADM as the dominant metaplastic route in this organ, which is what this node models.

PMID:17349585 SUPPORT Model Organism

"suggesting that PDA originates by differentiation of acinar/centroacinar cells or their precursors into ductal-like cells"

Lineage evidence that the ductal-like cells of PDAC descend from the acinar compartment, which is the transdifferentiation this node annotates.

PMID:26592447 SUPPORT Model Organism

"These data demonstrate that pancreatic ductal cells, whereas exhibiting relative resistance to oncogenic Kras alone, can serve as an effective cell of origin for pancreatic ductal adenocarcinoma in the setting of gain-of-function mutations in p53."

Ductal-origin mouse experiments refute exclusive acinar origin.

KRAS Oncogene Activation

Activating KRAS variants favor persistent RAS-GTP signaling through RAF-MEK-ERK and additional effector networks, supporting proliferation, survival, metabolic rewiring and microenvironmental remodeling. G12D, G12V and G12R are common in PDAC, with allele-specific signaling and inhibitor responses. Most PDACs are KRAS-mutant; KRAS-wild-type cancers require separate driver characterization. KRAS signaling does not itself establish acquisition of a particular tumor-suppressor mutation or therapeutic inhibition.

pancreatic acinar cell CL:0002064

Genetic context KRAS hgnc:6407 variant_origin: SOMATIC functional_impact_category: GAIN_OF_FUNCTION

Somatic activating KRAS codon-12 mutation, the initiating lesion of the PanIN-to-PDAC sequence, arising in the acinar/centroacinar compartment. The tumour's ductal phenotype is acquired downstream through acinar-to-ductal metaplasia and does not indicate a ductal cell of origin.

MAPK cascade GO:0000165 ↑ INCREASED phosphatidylinositol 3-kinase signaling GO:0043491 ↑ INCREASED cell population proliferation GO:0008283 ↑ INCREASED

Experimental models

Human PDAC Cell and Organoid RAS-Response Models ORGANOID Tests RAS-GTP-inhibitor signaling and growth response.

Downstream

Acinar-to-Ductal Metaplasia KRAS promotes persistent ductal reprogramming in susceptible acinar cells; injury, lineage and cooperating alterations modify this effect.

KRAS-Dependent Anabolic Glucose Metabolism Oncogenic KRAS regulates this growth-supporting metabolic program in the cited experimental context.

KRAS-Regulated Glutamine Redox Metabolism Oncogenic KRAS regulates this growth-supporting metabolic program in the cited experimental context.

Macropinocytic Protein Scavenging Oncogenic KRAS regulates this growth-supporting metabolic program in the cited experimental context.

KRAS-GM-CSF Myeloid Immunosuppression Oncogenic KRAS induces GM-CSF-dependent myeloid suppression.

USP20 Cholesterol-Metabolism CD8 Exhaustion Checkpoint KRAS-G12D induces EGR1-USP20, coordinating cholesterol metabolism and compensatory survival.

Show evidence (3 references)

PMID:35302596 SUPPORT Other

"KRAS mutation (MT) is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC)."

This directly supports KRAS as the central driver pathway in PDAC.

DOI:10.3389/fmed.2024.1369136 SUPPORT Other

"In the case of pancreatic ductal adenocarcinomas (PDAC), 90–92% harbor mutations in the oncogene KRAS, triggering canonical MAPK signaling."

Review-level estimate and signaling background; precise frequencies vary by assay and cohort.

DOI:10.1093/carcin/bgae064 SUPPORT Other

"PanIN development begins with Kirsten rat sarcoma viral oncogene (KRAS) mutations driving PanIN initiation. Key additional mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (TP53), and mothers against decapentaplegic homolog 4 (SMAD4) disrupt cell cycle control and..."

This review confirms KRAS mutations as the initiating event in PanIN development, with additional tumor suppressor losses driving progression to invasive carcinoma.

Tumor Suppressor Inactivation

Alterations of CDKN2A, TP53 and SMAD4 cooperate with oncogenic signaling. Loss of p16 removes restraint on CDK4/6-RB cell-cycle progression; p53 alterations weaken stress checkpoints and can confer context-dependent gain of function; SMAD4 loss changes TGF-beta responses. Reported alteration frequencies differ with cohort, assay, copy-number detection and inclusion of epigenetic silencing. These are cooperating events rather than consequences inferred from co-occurrence with KRAS.

regulation of cell cycle GO:0051726 ⚠ ABNORMAL apoptotic process GO:0006915 ↓ DECREASED DNA damage response GO:0006974 ⚠ ABNORMAL

Downstream

Pancreatic Precursor Progression and Invasive Growth Checkpoint and differentiation defects cooperate with KRAS to permit invasive progression.

Show evidence (1 reference)

PMID:18772397 SUPPORT Human Clinical

"This list includes the classic tumor suppressor genes CDKN2A (p16), SMAD4, and TP53, as well as genes that had not previously been implicated in pancreatic cancer development."

The landmark Jones et al. genomic analysis identified CDKN2A, SMAD4, and TP53 as core tumor suppressor genes in pancreatic cancer through global sequencing of 24 advanced pancreatic adenocarcinomas.

Pancreatic Precursor Progression and Invasive Growth

KRAS-mutant PanIN can progress with cooperating genetic and microenvironmental changes to invasive, gland-forming PDAC. IPMN and mucinous cystic neoplasms provide additional precursor routes. Not every precursor progresses, and a uniform obligatory mutation order or exclusive acinar origin is not established.

Downstream

Desmoplastic Stroma Tumor-secreted ligands promote fibroblast-state changes and matrix-producing stroma.

Metastatic Dissemination and Colonization Invasive growth enables dissemination, but the timing and route vary across tumors.

IL1-LIF-JAK-STAT Inflammatory Fibroblast Programming The neoplastic epithelial compartment can induce inflammatory fibroblast differentiation through secreted IL1α in PDAC organoid-stellate-cell systems. This branch represents signals from established tumors, not a claim that invasion itself or extracellular matrix deposition directly induces every iCAF state; other ligands contribute in vivo.

Tumor-Restraining Fibroblast Programs Neoplastic cells can establish a Hedgehog-responsive fibroblast-rich stroma with tumor-restraining activity in a genetically engineered PDAC mouse model. This incoming branch concerns the SHH-dependent component of the heterogeneous stromal node, not all fibroblast states or a universal protective role for fibrosis.

Pancreatic Exocrine Functional Loss An established pancreatic tumor can impair exocrine secretion through duct obstruction and loss of functional tissue. Risk depends on tumor location and extent; this is not an obligatory consequence of a noninvasive precursor, and postoperative insufficiency has an additional surgical cause.

Obstructive Jaundice An obstructive pancreatic head cancer can impair bile drainage and cause jaundice. This location-dependent consequence of established tumor growth is not attributed to all PDAC or to noninvasive precursors.

Show evidence (2 references)

PMID:17349585 SUPPORT Model Organism

"However, if these mice are challenged with a mild form of chronic pancreatitis, they develop the full spectrum of PanINs and invasive PDA."

Genetic and inflammatory cooperation supports progression in the defined mouse model.

PMID:26592447 SUPPORT Model Organism

"In contrast to the lack of response to oncogenic Kras alone, simultaneous activation of Kras and mutant p53 in adult ductal epithelium generated invasive PDAC in 75% of mice as early as 2.5 months after tamoxifen administration."

Cooperating oncogenic KRAS and mutant p53 enable invasive cancer in ductal-origin mice.

Desmoplastic Stroma

Tumor-derived signals and local tissue interactions recruit and alter fibroblast states that deposit collagen, hyaluronan and other extracellular matrix. Dense matrix can impair perfusion, but stromal programs are heterogeneous: some support inflammation or immune exclusion and others restrain tumor growth. Fibroblast depletion and matrix digestion are not interchangeable, and neither is a generally validated treatment for PDAC.

pancreatic stellate cell CL:0002410

extracellular matrix organization GO:0030198 ↑ INCREASED collagen biosynthetic process GO:0032964 ↑ INCREASED

Computational models

PDAC CAF-Mediated Invasion PhysiCell Model AGENT BASED PhysiCell Implements ECM-driven fibroblast motility and epithelial-mesenchymal state switching encoded in `config/cell_rules.csv` for the stromal invasion program.

Downstream

CAF-Mediated T Cell Exclusion The FAP-positive CXCL12-producing subset supports spatial immune exclusion.

Matrix-Associated Hypoperfusion Matrix accumulation can impair vascular perfusion.

Show evidence (1 reference)

PMID:30366930 SUPPORT Model Organism

"Here, we use organoid and mouse models to identify TGFβ and IL1 as tumor-secreted ligands that promote CAF heterogeneity."

Tumor-secreted signals establish heterogeneous stromal responses.

CAF-Mediated T Cell Exclusion

FAP-positive fibroblasts can supply CXCL12 that localizes around malignant cells and limits T-cell access. In KPC mouse tumors, CXCR4 inhibition rapidly increased T-cell accumulation and synergized with PD-L1 blockade. This identifies a specific stromal immune-exclusion circuit, not uniform behavior of all fibroblasts.

pancreatic stellate cell CL:0002410 CD8-positive, alpha-beta T cell CL:0000625

CXCL12 hgnc:10672 CXCR4 hgnc:2561 FAP hgnc:3590

chemokine-mediated signaling pathway GO:0070098 ↑ INCREASED Negative Regulation of T Cell Mediated Immunity GO:0002710 ↑ INCREASED

Downstream

Immune Evasion The specified mechanism limits effective antitumor T-cell control.

Show evidence (1 reference)

PMID:24277834 SUPPORT Model Organism

"Administering AMD3100, a CXCL12 receptor chemokine (C-X-C motif) receptor 4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with α-PD-L1 to greatly diminish cancer cells"

Perturbation supports CXCL12-CXCR4-mediated immune exclusion in a mouse PDAC model.

IL1-LIF-JAK-STAT Inflammatory Fibroblast Programming

Tumor-derived IL1 induces fibroblast LIF and JAK-STAT signaling, promoting an inflammatory CAF state. TGF-beta antagonizes this program by reducing IL1R1 and favoring myofibroblasts. Spatial exposure and plasticity generate distinct CAF niches, so fibroblast number alone is an inadequate mechanistic readout.

Show evidence (1 reference)

PMID:30366930 SUPPORT In Vitro

"We show that IL1 induces LIF expression and downstream JAK/STAT activation to generate inflammatory CAFs and demonstrate that TGFβ antagonizes this process by downregulating IL1R1 expression and promoting differentiation into myofibroblasts."

Directly distinguishes competing CAF programs.

Tumor-Restraining Fibroblast Programs

Some fibroblast and stromal programs constrain PDAC. Genetic SHH loss and depletion of alpha-SMA-positive myofibroblasts in distinct mouse models accelerated aggressive disease; newer interferon-response CAF work also identifies a restraining state. These findings qualify global stroma-removal strategies without proving that every myofibroblast state is protective.

Show evidence (2 references)

PMID:24856585 SUPPORT Model Organism

"Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth."

The primary genetic stromal-perturbation study establishes an important counterexample to uniformly tumor-promoting stroma.

PMID:24856586 SUPPORT Model Organism

"Suppressed immune surveillance with increased CD4(+)Foxp3(+) Tregs was observed in myofibroblast-depleted mouse tumors."

Myofibroblast depletion worsened mouse disease; intervention and source scope are explicit.

Matrix-Associated Hypoperfusion

Hyaluronan-rich stroma can elevate interstitial fluid pressure, collapse vessels and restrict delivery of nutrients and drugs in PDAC mouse models. Matrix degradation improved perfusion experimentally, but the phase III PEGPH20 trial did not improve survival, limiting direct therapeutic extrapolation.

Show evidence (1 reference)

PMID:22439937 SUPPORT Model Organism

"We show here that this desmoplastic reaction generates inordinately high interstitial fluid pressures (IFPs), exceeding those previously measured or theorized for solid tumors, and induces vascular collapse, while presenting substantial barriers to perfusion, diffusion, and convection of small..."

Primary mouse study supports a physical stromal barrier.

KRAS-Dependent Anabolic Glucose Metabolism

KRAS supports glucose uptake and redirects intermediates toward anabolic pathways that sustain pancreatic tumor growth. This is a regulated metabolic program rather than a universal switch eliminating oxidative phosphorylation.

glycolytic process GO:0006096 ↑ INCREASED

Downstream

Pancreatic Precursor Progression and Invasive Growth Nutrient use and redox support permit continued malignant growth.

Show evidence (1 reference)

PMID:22541435 SUPPORT Model Organism

"Transcriptome and metabolomic analyses indicate that Kras(G12D) serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP)."

Genetic KRAS withdrawal and metabolic profiling establish the growth-supporting program.

KRAS-Regulated Glutamine Redox Metabolism

In studied PDAC cells, glutamine-derived aspartate is routed through cytosolic GOT1, malate and pyruvate to support NADPH-dependent redox balance. Dependency varies with growth context and compensatory metabolism; this does not establish clinical efficacy of glutaminase inhibition.

GOT1 hgnc:4432

Downstream

Pancreatic Precursor Progression and Invasive Growth Nutrient use and redox support permit continued malignant growth.

Show evidence (1 reference)

PMID:23535601 SUPPORT In Vitro

"Furthermore, we establish that the reprogramming of glutamine metabolism is mediated by oncogenic KRAS"

Genetic experiments connect KRAS to the noncanonical glutamine pathway.

Macropinocytic Protein Scavenging

RAS-driven macropinocytosis internalizes extracellular protein for lysosomal proteolysis and amino-acid supply. It supports growth in nutrient-poor settings and is observed in primary human PDAC specimens, complementing transport of free nutrients.

macropinocytosis GO:0044351 ↑ INCREASED

Downstream

Pancreatic Precursor Progression and Invasive Growth Nutrient use and redox support permit continued malignant growth.

Show evidence (2 references)

PMID:23665962 SUPPORT In Vitro

"The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism."

Protein uptake supplies usable metabolites in Ras-transformed cellular models.

PMID:25644265 SUPPORT Human Clinical

"Consistent with this hypothesis, active macropinocytosis is observed in primary human PDAC specimens."

Human tissue supports relevance, without establishing universal flux or dependency.

Autophagy-Lysosome Growth Support

Basal autophagy can maintain oxidative metabolism and restrain damaging reactive oxygen species in established pancreatic cancer models. Recycling also provides substrates under treatment stress. The effects of autophagy loss differ by tumor stage and genetic context; preclinical dependency is not a validated universal treatment response.

autophagy GO:0006914 ↑ INCREASED

Downstream

Pancreatic Precursor Progression and Invasive Growth Autophagic recycling and redox control support established tumor growth.

Show evidence (1 reference)

PMID:21406549 SUPPORT In Vitro

"Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species, elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation."

Direct perturbation demonstrates metabolic support in the tested PDAC cells.

Immune Evasion

Myeloid suppression, dysfunctional lymphocytes, stromal exclusion and impaired antigen presentation limit immune control in most PDAC. These mechanisms vary between tumors and metastatic sites. Rare mismatch-repair-deficient/MSI-high cancers can respond to checkpoint blockade; PDAC is not uniformly refractory to every immune or targeted therapy.

regulatory T cell CL:0000815 tumor-associated macrophage CL:0000235

immune response GO:0006955 ↓ DECREASED

Computational models

PDAC Immunotherapy PhysiCell Model AGENT BASED PhysiCell Encodes PD-L1-dependent suppression of T-cell motility and attack probabilities, plus macrophage inflammatory-state rules, in `config/cell_rules.csv`.

Show evidence (2 references)

DOI:10.1186/s12943-023-01813-y SUPPORT Human Clinical

"Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival."

This review establishes immunosuppression as a hallmark of PDAC that contributes to metastasis and poor survival, supporting the immune evasion mechanism.

DOI:10.1186/s12943-023-01813-y SUPPORT Human Clinical

"Following chemokine and exosomal guidance, these cells metastasize to the organ-specific pre-metastatic niches (PMNs) constituted by local resident cells, stromal fibroblasts, and suppressive immune cells, such as the metastasis-associated macrophages, neutrophils, and myeloid-derived suppressor cells."

This describes the immune cell populations in PDAC metastatic niches including macrophages, neutrophils, and MDSCs that constitute the immunosuppressive microenvironment.

KRAS-GM-CSF Myeloid Immunosuppression

Oncogenic KRAS induces tumor-cell GM-CSF, expanding suppressive myeloid cells that constrain cytotoxic T-cell immunity in pancreatic neoplasia models. This supplies a disease-driving counterpart to the myeloid remodeling seen after KRAS inhibition.

CSF2 hgnc:2434

Downstream

Immune Evasion The specified mechanism limits effective antitumor T-cell control.

Show evidence (1 reference)

PMID:22698407 SUPPORT Model Organism

"Kras(G12D)-dependent production of GM-CSF in vivo is required for the recruitment of Gr1(+)CD11b(+) myeloid cells."

Primary mechanistic study links oncogenic KRAS to GM-CSF-dependent immune suppression.

NBR1-Mediated MHC-I Autophagic Degradation

Selective autophagy directs MHC-I to lysosomes through NBR1, reducing surface antigen presentation and immune recognition in PDAC models. Autophagy inhibition can restore MHC-I and improve T-cell control. This can coexist with RAS-dependent and FAK-dependent regulation; pathway dominance or mutual independence has not been established.

NBR1 hgnc:6746

Downstream

Immune Evasion The specified mechanism limits effective antitumor T-cell control.

Show evidence (1 reference)

PMID:32376951 SUPPORT Model Organism

"Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1."

Primary study establishes selective antigen-presentation loss through autophagy.

FAK-Mediated Antigen-Presentation Suppression

Mechanism confidence: Provisional

Tumor-cell FAK signaling limits immunoproteasome expression and antigen presentation in PDAC models. FAK depletion increases antigen diversity and MHC-I presentation; combined STAT3 loss further promotes immune control. This is a complementary regulator, not evidence that RAS cannot influence MHC-I. The reported antigen-presentation effect is kinase-independent, requires nuclear FAK, and is lost in an extreme squamous phenotype; FAK kinase inhibition is therefore not equivalent to eliminating this function.

PTK2 hgnc:9611

Downstream

Immune Evasion The specified mechanism limits effective antitumor T-cell control.

Show evidence (1 reference)

PMID:36977556 SUPPORT In Vitro

"Loss of PDAC cell-intrinsic FAK signalling promotes expression of the immunoproteasome and Major Histocompatibility Complex class-I (MHC-I), resulting in increased antigen diversity and antigen presentation by FAK-/- PDAC cells."

The primary study evaluates FAK-dependent immune regulation in pancreatic cancer models.

Exosome-MIF Liver Premetastatic Niche

PDAC-derived exosomes carrying MIF can be taken up by Kupffer cells, inducing TGF-beta, hepatic stellate-cell fibronectin deposition and recruitment of bone-marrow-derived macrophages. This establishes a liver premetastatic niche mechanism; the cited study does not by itself establish direct exosomal suppression of dendritic cells or T cells.

pancreatic ductal cell CL:0002079 Kupffer cell CL:0000091 recruited bone marrow-derived macrophage CL:0000235

extracellular exosome biogenesis GO:0097734 ↑ INCREASED transforming growth factor beta production GO:0071604 ↑ INCREASED

Downstream

Metastatic Dissemination and Colonization MIF-dependent Kupffer-cell and stellate-cell remodeling supports liver colonization.

Show evidence (2 references)

PMID:25985394 SUPPORT Model Organism

"Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages."

The primary study supports exosomal MIF-driven liver niche formation and metastasis, not direct proof of lymphocyte suppression.

PMID:25985394 SUPPORT Model Organism

"We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis."

The primary study supports exosomal MIF-driven liver niche formation and metastasis, not direct proof of lymphocyte suppression.

Metastatic Dissemination and Colonization

Invasive tumor cells disseminate and establish distant lesions, frequently in the liver and also lung or peritoneum. Colonization depends on both tumor-cell programs and organ-specific niches; metastatic-site immune composition differs from the primary tumor. A single EMT program is not obligatory for every metastatic event.

Downstream

Hepatic Metastases Hepatic colonization is a common site-specific manifestation among patients presenting with metastatic PDAC.

Show evidence (1 reference)

PMID:25985394 SUPPORT Model Organism

"Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden."

The primary study experimentally connects extracellular vesicles to a permissive liver niche.

Early Dissemination and EMT

Epithelial-mesenchymal plasticity can accompany dissemination and drug resistance, but individual EMT transcription factors have nonredundant roles. Snail or Twist deletion did not abolish metastasis in a KPC study. Early dissemination observed in mouse precursor models is not proof that all human PDAC metastasizes before invasion.

epithelial to mesenchymal transition GO:0001837 ↑ INCREASED cell migration GO:0016477 ↑ INCREASED

Show evidence (2 references)

PMID:22265420 SUPPORT Model Organism

"Tagged cells invaded and entered the bloodstream unexpectedly early, before frank malignancy could be detected by rigorous histologic analysis; this behavior was widely associated with epithelial-to-mesenchymal transition (EMT)."

Lineage tracking establishes early dissemination in a mouse pancreatic-cancer model, not universal timing of human metastasis.

PMID:26560028 SUPPORT Model Organism

"EMT suppression in the primary tumour does not alter the emergence of invasive PDAC, systemic dissemination or metastasis."

Snail/Twist deletion challenges obligatory EMT in this mouse model; it does not show that all EMT programs are irrelevant.

Perineural Invasion

Pancreatic cancer cells interact with nerves and migrate along neural structures. HGF-MET signaling can activate mTOR-NGF, promoting nerve recruitment and invasion in experimental models. PNI is associated with adverse clinical outcomes and can contribute to pain; it is not established as the universal route to distant metastasis. Human NGF/TrkA levels correlate with PNI and pain in one tissue cohort, but a prospective resectable cohort found pain did not predict PNI; clinical pain and neural invasion are not interchangeable readouts.

positive regulation of cell migration GO:0030335 ↑ INCREASED

Show evidence (4 references)

PMID:35449152 SUPPORT In Vitro

"Activating the HGF/c-Met signaling pathway potentiated the expression of nerve growth factor (NGF) to recruit nerves and promote the PNI."

Direct perturbation supports tumor-nerve crosstalk.

PMID:35449152 SUPPORT Model Organism

"we found that knocking down c-Met expression inhibited cancer cell migration along the nerve, reduced the damage of the sciatic nerve caused by cancer cells and protected the function of the sciatic nerve in vivo."

Mouse nerve-invasion experiments support local injury, not a clinical pain-frequency estimate.

PMID:10561305 SUPPORT Human Clinical

"Enhanced expression of the NGF/TrkA system may influence perineural invasion and may contribute to the pain syndrome in human pancreatic cancer."

Human tissue association supports biological relevance while preserving the authors causal uncertainty.

+ 1 more reference

Immunosuppressive TME Reversibility under RAS(ON) Inhibition

In immunocompetent PDAC models, RAS(ON) multiselective inhibition can reduce suppressive myeloid subsets, increase tumor MHC-I and lymphocyte infiltration, and enable immune-dependent tumor control. RMC-7977 and daraxonrasib provide direct PDAC evidence. Responses and optimal checkpoint partners are model-dependent; increased Tregs and adaptive myeloid rebound can limit benefit. Patient survival from daraxonrasib monotherapy does not establish an immune-mediated clinical benefit.

Animal models

Immunocompetent Mouse PDAC RAS-Inhibition Models Mouse perturbs Measures immune remodeling and depletion-defined immune contribution.

Show evidence (2 references)

PMID:40057911 SUPPORT Model Organism

Direct PDAC evidence was omitted from the immune report despite being cited in the resistance report.

PMID:40057911 SUPPORT Model Organism

"The depth and duration of tumor regression depended on T cells and conventional dendritic cells."

Depletion/genetic experiments establish immune contribution in mouse PDAC.

Cyclophilin A Loss and Reduced Tri-Complex Engagement

Mechanism confidence: Provisional

A preprint reports reduced cyclophilin-A protein with retained KRAS-G12D-GTP signaling in daraxonrasib-resistant PDAC cells. As cyclophilin A is required for tri-complex formation, reduced availability is a plausible drug-engagement escape mechanism. This observation does not establish that peptidyl-prolyl isomerase catalytic activity was measured or is causally required. The single clinical case in this paper instead concerns KRAS-G12R EGFR/wild-type-RAS activation.

Acquired Resistance to RAS(ON) Multiselective Inhibition

PPIA hgnc:9253

Downstream

Acquired RAS(ON) Inhibitor Resistance Under the specified RAS-inhibitor exposure, this route can sustain tumor growth or reduce target inhibition. Source and regimen restrictions apply.

Show evidence (1 reference)

PMID:42465401 SUPPORT In Vitro

"In contrast, KRAS G12D resistance arose through retained KRAS G12D -GTP signaling, with a decrease of cyclophilin A (CypA) protein, the binding partner required for daraxonrasib activity."

Preprint cellular evidence for cyclophilin-A protein loss in the G12D context.

RAS-Independent Cell-Cycle Uncoupling

Mechanism confidence: Provisional

A preprint describes acquired RMC-6236 resistance in mixed PDAC and NSCLC models with sustained cell-cycle progression despite RAS suppression. CDK4/6 or CDK2 cotargeting restored control through distinct arrest programs; CDK2 inhibition produced more durable cytostasis in the tested settings. This is not a clinically validated combination or proof that simultaneous inhibition of all three kinases is required. CDK8-mediated microenvironmental resistance is a separate mechanism.

Acquired Resistance to RAS(ON) Multiselective Inhibition

cell population proliferation GO:0008283 ↑ INCREASED

Downstream

Acquired RAS(ON) Inhibitor Resistance Under the specified RAS-inhibitor exposure, this route can sustain tumor growth or reduce target inhibition. Source and regimen restrictions apply.

Show evidence (2 references)

PMID:41959066 SUPPORT In Vitro

"While these pathways can be broadly inhibited using the pan-RAS-ON inhibitor RMC-6236, cells remained capable of developing acquired resistance where cell proliferation is uncoupled from RAS signaling."

Preprint directly models RMC-6236 resistance in cellular systems.

PMID:41959066 SUPPORT Model Organism

"Finally, concurrent inhibition of KRAS with either CDK4/6 or CDK2 yields durable tumor control in vivo in xenografts derived from acquired resistant models."

Xenograft validation supports preclinical cell-cycle cotargeting, with kinase-specific responses.

Acquired RAS(ON) Inhibitor Resistance

Daraxonrasib can initially control PDAC and subsequently lose efficacy through heterogeneous resistance routes. An August 2026 study profiled 44 patients with response or stable disease lasting more than three months followed by progression: 59% had treatment-emergent RAS-pathway genomic alterations, including KRAS amplification in 36%. Mutant-allele identity was inferred from variant-allele-frequency ratios by an exploratory method, not directly confirmed in all cases. These selected-cohort findings establish patient mechanisms but not universal resistance or population-wide route frequencies. Median progression-free survival alone cannot distinguish acquired resistance, primary nonresponse and death. Non-genomic, tissue-specific and low-shedding routes remain incompletely captured.

Show evidence (4 references)

PMID:42581230 SUPPORT Human Clinical

August 2026 paired clinical sequencing supersedes the July reports and earlier assessment claim that no longitudinal clinical characterization was available.

PMID:42581230 SUPPORT Human Clinical

"Notably, no acquired secondary KRAS mutations were observed, distinct from resistance profiles of mutant-selective KRAS G12C(OFF) inhibitors."

No secondary KRAS mutations were found in this selected PDAC cohort; this is not proof that such mutations are impossible.

+ 1 more reference

On-Target RAS Reactivation and KRAS Amplification

Mechanism confidence: Provisional

Increased mutant KRAS dosage can attenuate daraxonrasib suppression and restore RAS-pathway output in PDAC models. Paired ctDNA detected emergent KRAS amplification in 16/44 profiled PDAC patients after initial disease control. Assignment to the pre-existing mutant allele was inferred from variant-allele-frequency ratios; the supplementary table explicitly calls this exploratory and unconfirmed, rather than direct allele phasing in all cases. Engineered and selected PDAC models provide functional corroboration of mutant KRAS dosage. Secondary KRAS mutations were absent from the 44 PDAC cases and selected PDAC resistance models, while an engineered Ba/F3 deep mutational scan identified resistance-conferring second-site variants in a different context.

Acquired Resistance to RAS(ON) Multiselective Inhibition

Downstream

Acquired RAS(ON) Inhibitor Resistance Under the specified RAS-inhibitor exposure, this route can sustain tumor growth or reduce target inhibition. Source and regimen restrictions apply.

Show evidence (3 references)

PMID:42581230 SUPPORT Human Clinical

"Method is exploratory, and allele amplification is not confirmed."

Supplementary Table 3 qualifies mutant-versus-wild-type assignment from relative variant allele frequencies. This limitation does not negate the observed 16/44 KRAS amplification calls.

PMID:42581230 SUPPORT Model Organism

"To corroborate these clinical findings, we found, or mechanistically established, concordant mechanisms of daraxonrasib resistance in human and murine preclinical models of PDAC, including mutant KRAS and MYC amplification and RTK upregulation, with these alterations guiding various combination..."

Preclinical perturbation corroborates selected clinical candidate routes; it does not establish causality for every observed co-alteration.

RTK and Feedback Pathway Reactivation

Mechanism confidence: Provisional

RTK signaling can contribute to daraxonrasib resistance in particular PDAC contexts. The paired 44-patient study found emergent RTK alterations in 4/44, with HER2-upregulated resistant models providing functional support. A separate preprint identified EGFR/wild-type-RAS activation in KRAS-G12R models and one patient who progressed after ten months. G12D cyclophilin-A loss is a distinct route. Earlier MEK or G12C-selective-inhibitor studies are contextual analogies and do not establish universal sufficiency against multiselective inhibition.

Acquired Resistance to RAS(ON) Multiselective Inhibition

Downstream

Acquired RAS(ON) Inhibitor Resistance Under the specified RAS-inhibitor exposure, this route can sustain tumor growth or reduce target inhibition. Source and regimen restrictions apply.

Show evidence (4 references)

PMID:42581230 SUPPORT Human Clinical

PMID:42465401 SUPPORT In Vitro

"KRAS G12R is marked by its inability to transactivate RAS WT , and it was observed that daraxonrasib resistant KRAS G12R PDAC cells utilize EGFR/RAS WT -GTP signaling as the dominant adaptive route."

Preprint supports an allele-specific cellular route; it should not be generalized to all KRAS alleles.

PMID:42465401 SUPPORT Human Clinical

"a KRAS G12R PDAC patient who progressed after 10 months on daraxonrasib showed intratumoral EGFR/RAS WT activation"

One-patient molecular observation, supplemented by ex-vivo toroid modeling; subsequent multiagent salvage cannot isolate trametinib benefit.

+ 1 more reference

Adaptive mTOR and JUN-AP1 Transcriptional Program

Mechanism confidence: Provisional

CRISPR screens identify mTOR and JUN as convergent mediators of resistance to MAPK-pathway inhibitor combinations. In PDAC cells, JUN overexpression supported resistance to SHP2 plus RMC-6236; in-vivo MAP2K4 rescue used SHP2 plus ERK inhibition. The combination-specific evidence should not be recast as patient-level daraxonrasib monotherapy resistance. A separate RMC-7977 mouse study identified focal Jun gain in one resistant tumor.

Acquired Resistance to RAS(ON) Multiselective Inhibition

Downstream

Acquired RAS(ON) Inhibitor Resistance Under the specified RAS-inhibitor exposure, this route can sustain tumor growth or reduce target inhibition. Source and regimen restrictions apply.

Show evidence (2 references)

PMID:41572361 SUPPORT In Vitro

"Through unbiased CRISPR-based screenings, we identified mTOR and JUN hyperactivation as interconnected mechanisms that overcome MAPK suppression."

CRISPR and follow-up cellular experiments support the combination-treatment scope.

PMID:41572361 SUPPORT In Vitro

"Alterations in the PI3K/AKT/mTOR and JUN pathways can induce resistance to multiple combinations of MAPK pathway inhibitors"

The study conclusion explicitly concerns combinations, not a proven universal monotherapy escape mechanism.

Mitochondrial Remodeling and Ferroptosis Vulnerability

Mechanism confidence: Provisional

Dual SHP2-MEK inhibition produces persistent mitochondrial changes and lipid-peroxide-defense dependency in PDAC models, with confirmation under direct RAS targeting. Sensitivity to GPX4 disruption is an exploitable treatment-induced vulnerability; it does not mean ferroptosis is already increased or that this state itself causes clinical daraxonrasib resistance. The primary intervention and model context are retained.

Show evidence (1 reference)

PMID:41545339 SUPPORT In Vitro

"We found that dual SHP2/mitogen-activated protein kinase kinase (MEK1/2) inhibition induces major alterations in mitochondrial mass and function, impacts reactive oxygen species (ROS) homeostasis and triggers lipid peroxidase dependency."

The primary experiment concerns vertical SHP2-MEK blockade.

MYC Amplification-Driven RAS-Independent Proliferation

Mechanism confidence: Provisional

RMC-7977-resistant KPC tumors frequently gained Myc copies while maintaining ERK suppression. YAP-TEAD-dependent transcriptional output accompanied resistance, and TEAD cotargeting restored sensitivity in vitro. The subsequent daraxonrasib clinical study detected MYC amplification in one patient together with KRAS amplification and corroborated MYC-related resistance in models. These data support a bypass route without proving that all MYC gain is independent of RAS or that TEAD combinations benefit patients.

Acquired Resistance to RAS(ON) Multiselective Inhibition

MYC hgnc:7553 YAP1 hgnc:16262

Animal models

KPC RMC-7977 Acquired-Resistance Models Mouse perturbs Tracks relapse-associated MYC amplification and downstream bypass.

Downstream

Acquired RAS(ON) Inhibitor Resistance Under the specified RAS-inhibitor exposure, this route can sustain tumor growth or reduce target inhibition. Source and regimen restrictions apply.

Show evidence (2 references)

PMID:38588697 SUPPORT Model Organism

"Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro."

Primary 2024 RMC-7977 study supplies stronger support than the systematic review cited by OpenScientist.

PMID:42581230 SUPPORT Human Clinical

"We also observed truncating mutations in NF1 (2 of 44; 4%), KEAP1 (2 of 44; 4%), a PTPN11 mutation or MYC amplification in one patient each (1 of 44; 2%)."

MYC alteration occurs in one selected clinical case; co-occurrence and small numbers limit attribution.

Myeloid Suppression Relief and CD8 Effector Infiltration

MRTX1133 and RAS(ON) multiselective inhibitors can reduce suppressive myeloid subsets and increase effector lymphocytes in immunocompetent PDAC models. Total macrophage abundance can increase while state composition changes; myeloid remodeling is not equivalent to depletion of every myeloid cell. The direction and durability of individual populations vary by agent, model and time.

RAS(ON) Inhibition Remodels the Immunosuppressive Microenvironment

CD8-positive effector T cell CL:0000625 ↑ INCREASED

Downstream

Immunosuppressive TME Reversibility under RAS(ON) Inhibition The observed treatment-induced change contributes to immune recognition or immune-dependent tumor control in the specified model.

Show evidence (2 references)

PMID:40057911 SUPPORT Model Organism

Direct PDAC evidence was omitted from the immune report despite being cited in the resistance report.

PMID:37625401 SUPPORT Model Organism

"MRTX1133 reverses early PDAC growth, increases intratumoral CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer-associated fibroblasts."

Final peer-reviewed MRTX1133 paper; its preprint PMID36824971 is not independent replication.

Tumor-Cell FAS Induction and CD8-Mediated Killing

Mechanism confidence: Provisional

KRAS-G12D inhibition by MRTX1133 induces FAS in malignant cells and patient-derived organoids, permitting CD8-mediated killing in PDAC models. This is drug- and model-specific evidence; the original citation to the preprint has been replaced with the final paper. CDK8-dependent FAS suppression can later oppose this response.

RAS(ON) Inhibition Remodels the Immunosuppressive Microenvironment

Downstream

Immunosuppressive TME Reversibility under RAS(ON) Inhibition The observed treatment-induced change contributes to immune recognition or immune-dependent tumor control in the specified model.

Show evidence (1 reference)

PMID:37625401 SUPPORT In Vitro

"Mechanistically, inhibition of KRASG12D in advanced PDAC and human patient derived organoids induces FAS expression in cancer cells and facilitates CD8+ T cell-mediated death."

The final primary report directly supports FAS induction and killing, including human organoid experiments.

Antigen Presentation Restoration

Mechanism confidence: Provisional

RMC-7977 increased MHC-I on residual malignant cells in a syngeneic PDAC model. This is direct evidence for a RAS(ON)-associated antigen-presentation change in PDAC, although the relative mediation by autophagy, FAK, interferon signaling and tumor selection remains unresolved. NSCLC daraxonrasib-elironrasib results are supplementary cross-cancer evidence, not the sole anchor.

RAS(ON) Inhibition Remodels the Immunosuppressive Microenvironment

antigen processing and presentation GO:0019882 ↑ INCREASED

Downstream

Immunosuppressive TME Reversibility under RAS(ON) Inhibition The observed treatment-induced change contributes to immune recognition or immune-dependent tumor control in the specified model.

Show evidence (1 reference)

PMID:40057911 SUPPORT Model Organism

"the tumor cells that remained exhibited increased expression of MHC class I"

Flow-cytometric on-treatment finding in 6419c5 PDAC tumors after RMC-7977; this does not establish the precise molecular mediator.

USP20 Cholesterol-Metabolism CD8 Exhaustion Checkpoint

Mechanism confidence: Provisional

KRAS-G12D induces EGR1-USP20, stabilizing HMG-CoA reductase and promoting cholesterol metabolism associated with CD8 exhaustion. KRAS inhibition or cholesterol blockade induces compensatory ULK1-associated autophagy; USP20 also stabilizes ULK1. This is a two-arm metabolic and survival mechanism. MRTX1133 plus USP20 inhibition and PD-1 blockade regressed tumors in preclinical models, but human tissue profiling is not evidence of clinical combination efficacy.

RAS(ON) Inhibition Remodels the Immunosuppressive Microenvironment

Downstream

Immune Evasion Cholesterol-associated dysfunction contributes to CD8 exhaustion.

Autophagy-Lysosome Growth Support USP20 stabilizes ULK1 and supports compensatory autophagy under KRAS-G12D or cholesterol inhibition.

Show evidence (2 references)

PMID:42392864 SUPPORT In Vitro

"Mechanistically, KRASG12D transcriptionally upregulated USP20 via EGR1, which simultaneously deubiquitinated and stabilised 3-hydroxy-3-methylglutaryl-CoA reductase and ULK1, thereby orchestrating cholesterol metabolism and autophagy-associated survival."

Mechanistic preclinical experiments relate USP20 to cholesterol and autophagy; the cohort provides human-tissue context.

PMID:42392864 SUPPORT Model Organism

"In preclinical PDAC models, triple therapy with GSK2643943A, MRTX1133 and anti-PD-1 elicited a robust therapeutic response and induced significant tumour regression."

Mouse combination activity remains investigational.

CDK8-CXCL2 Adaptive Immune Reversal

Mechanism confidence: Provisional

Long-term MRTX1133 treatment can reverse early immune infiltration through CDK8-associated CXCL2 secretion and FAS suppression. CDK8 perturbation restores immune control in those PDAC models. Daraxonrasib-resistant PDX tumors also show CDK8 upregulation, but this does not establish the entire temporal CXCL2/FAS immune circuit under daraxonrasib or in patients.

Acquired Resistance to RAS(ON) Multiselective Inhibition RAS(ON) Inhibition Remodels the Immunosuppressive Microenvironment

Downstream

Immune Evasion Under prolonged MRTX1133 exposure, CXCL2 and FAS changes restore immune suppression.

Show evidence (2 references)

PMID:42436354 SUPPORT Model Organism

"CDK8 imparts this resistance via induction of CXCL2 chemokine secretion, inhibition of FAS expression, and remodeling of the TME to promote immune evasion."

The mechanistic immune reversal was tested chiefly during MRTX1133 treatment.

PMID:42436354 SUPPORT Model Organism

"We also provide evidence of CDK8 upregulation in PDX tumors resistant to inhibitors selective for RAS(ON) and RASG12D(ON): daraxonrasib and zoldonrasib, respectively"

PDX expression supports a shared candidate node, without proving drug-specific immune mediation.

Regulatory T-Cell Recruitment after KRAS Inhibition

Mechanism confidence: Provisional

An August 2026 PDAC study found that MRTX1133 or daraxonrasib recruits regulatory as well as effector and exhausted T cells. In its models, CTLA-4 blockade reprogrammed effector Tregs, reduced CD8 exhaustion and supported tertiary lymphoid structures. Other checkpoint combinations were less effective. This contrasts with a different RMC-7977 model where the CD4 increase was not attributable to FoxP3-positive Tregs, so generalized Treg relief is not supported.

regulatory T cell CL:0000815

Show evidence (2 references)

DOI:10.1038/s41467-026-75960-3 SUPPORT Model Organism

"Here, we demonstrate that Kras* targeting using MRTX1133 or Daraxonrasib recruits diverse T-cell infiltrates, including regulatory (Tregs), effector and exhausted T cells into the PDAC microenvironment."

Newer mouse PDAC evidence replaces the unsupported positive Treg-relief node.

PMID:40057911 SUPPORT Model Organism

"the increase in CD4+ T cells upon RMC-7977 treatment was not attributable to this population"

In this separate model the CD4 expansion did not reflect FoxP3-positive Tregs, illustrating model dependence.

IL6-CAF and Myeloid Rebound after SOS1-MEK Inhibition

Mechanism confidence: Provisional

SOS1 plus MEK blockade increased CD8 infiltration but also generated IL6-positive inflammatory CAFs, M2-like macrophages and poorer dendritic-cell function in KPCY models. CD40 agonism reactivated myeloid cells and enabled durable checkpoint combinations. This qualifies a uniformly beneficial RAS-inhibition model but is not direct daraxonrasib evidence.

RAS(ON) Inhibition Remodels the Immunosuppressive Microenvironment

Downstream

Immune Evasion Stromal and myeloid adaptation can limit the benefit of initial T-cell entry.

Show evidence (1 reference)

PMID:38727236 SUPPORT Model Organism

"revealed an increase in inflammatory cancer-associated fibroblasts (iCAF), M2 macrophages, and a decreased dendritic cell (DC) quality"

Single-cell and perturbation work establishes a counter-regulatory microenvironment under SOS1-MEK blockade.

Basal-State GM-CSF Immunosuppressive Circuit

Mechanism confidence: Provisional

Basal malignant cells can organize tumor-maintaining fibroblast, macrophage and cytokine states. Lineage tracing found greater plasticity of basal than classical cells in autochthonous mouse PDAC. Basal-state ablation, and separately basal-cell GM-CSF knockout, reprogrammed the stroma and recruited cytotoxic lymphocytes. This establishes a causal circuit in these models while leaving human state-targeting efficacy unresolved.

CSF2 hgnc:2434

Downstream

Immune Evasion Basal-cell GM-CSF maintains an immunosuppressive tumor ecosystem in autochthonous mouse PDAC.

Show evidence (1 reference)

PMID:42523238 SUPPORT Model Organism

"Knockout of a single cytokine, GM-CSF, specifically in basal cells recapitulated macrophage repolarization and lymphocyte recruitment observed upon basal state ablation and shrank tumors."

Basal-cell-specific genetic perturbation establishes an immune-organizing GM-CSF role in mouse PDAC. Human prognostic association does not establish the same intervention effect.

Pancreatic Exocrine Functional Loss

Tumor-associated obstruction and loss of functional pancreatic tissue can impair digestive enzyme delivery. The resulting maldigestion contributes to nutritional loss; this process also occurs after pancreatic surgery. Clinical prevalence varies with stage, location and testing method.

Downstream

Exocrine Pancreatic Insufficiency Loss of digestive enzyme delivery produces clinical pancreatic exocrine insufficiency.

Weight Loss Maldigestion is one contributor to weight loss in advanced pancreatic cancer.

Show evidence (1 reference)

PMID:32631175 SUPPORT Human Clinical

"The pooled prevalence of pancreatic exocrine insufficiency in advanced pancreatic cancer was 72% (95% confidence interval: 55-86%)"

Meta-analysis supports substantial exocrine insufficiency specifically in advanced pancreatic cancer; heterogeneity and tumor location limit generalization to all PDAC.

Adaptive CD24 Antiphagocytic Signaling

Mechanism confidence: Provisional

In KRAS-G12C-driven mouse PDAC, selective KRAS inhibition upregulated the CD24 antiphagocytic signal despite an inflamed microenvironment. CD24 blockade increased macrophage phagocytosis and sensitized tumors; related findings occurred in G12D PDAC. The preprint and final paper report the same work. This is a plausible immune-adaptation route whose relevance to clinical daraxonrasib progression remains unproven.

Acquired Resistance to RAS(ON) Multiselective Inhibition RAS(ON) Inhibition Remodels the Immunosuppressive Microenvironment

CD24 hgnc:1645

Downstream

Immune Evasion Induced CD24 reduces macrophage-mediated tumor-cell clearance in selective-KRAS-inhibitor models.

Show evidence (1 reference)

PMID:40966362 SUPPORT Model Organism

"Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment."

Functional antibody perturbation supports CD24-mediated adaptation in G12C/G12D-selective-inhibitor PDAC models, not a proven clinical daraxonrasib-resistance route.

Senescent Myofibroblast Immunosuppression

Mechanism confidence: Provisional

Senescent myofibroblastic CAFs accumulate near tumor ducts and during PDAC progression. Genetic or pharmacologic depletion of senescent stromal cells in mouse models reduced macrophage-associated immune suppression and improved chemotherapy responsiveness. Human tissue identifies the state, but clinical senolytic efficacy is not established.

Downstream

Immune Evasion Senescent stromal programs maintain macrophage-mediated immune suppression in PDAC models.

Show evidence (1 reference)

DOI:10.1158/2159-8290.CD-23-0428 SUPPORT Model Organism

"Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy."

Mouse senescent-stroma perturbation supports a specific promoting CAF state, complementary to tumor-restraining fibroblast programs.

✶

Histopathology

Malignant Glandular Differentiation

Infiltrative malignant epithelial glands with ductal differentiation; differentiation can vary and this morphology does not establish an exclusively ductal cell of origin.

Desmoplastic Stroma

Dense collagen-rich fibrotic stroma surrounding malignant glands is a defining histopathologic feature of PDAC.

Show evidence (1 reference)

PMID:30366930 SUPPORT Model Organism

"Here, we use organoid and mouse models to identify TGFβ and IL1 as tumor-secreted ligands that promote CAF heterogeneity."

Tumor-secreted signals establish heterogeneous stromal responses.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Digestive 4

Pancreatic Adenocarcinoma OBLIGATE HP:0006725

Obstructive Jaundice Cholestasis HP:0001396

Show evidence (1 reference)

PMID:25726049 SUPPORT Other

"Common signs and symptoms of PDA include abdominal or back pain, jaundice, weight loss, pruritus, and nausea/vomiting."

The diagnostic review supports presentation but provides no numerical frequency denominator.

Hepatic Metastases Neoplasm of the liver HP:0002896

Show evidence (1 reference)

PMID:36776324 SUPPORT Human Clinical

"There was a highest incidence of liver metastases from pancreatic cancer (2387,74.36%), followed by lung (625,19.47%), bone (190,5.92%), and brain (8,0.25%)."

This population-based study of metastatic PDAC directly identifies liver metastases as the most common distant metastatic site at diagnosis.

Exocrine Pancreatic Insufficiency HP:0001738

Show evidence (1 reference)

PMID:32631175 SUPPORT Human Clinical

"The pooled prevalence of pancreatic exocrine insufficiency in advanced pancreatic cancer was 72% (95% confidence interval: 55-86%)"

Meta-analysis supports substantial exocrine insufficiency specifically in advanced pancreatic cancer; heterogeneity and tumor location limit generalization to all PDAC.

Endocrine 1

New-Onset Diabetes Diabetes mellitus HP:0000819

Show evidence (1 reference)

PMID:28507210 SUPPORT Other

"The relationships between diabetes and pancreatic ductal adenocarcinoma (PDAC) are complex. Longstanding type 2 diabetes (T2DM) is a risk factor for pancreatic cancer, but increasing epidemiological data point to PDAC as also a cause of diabetes due to unknown mechanisms."

Andersen et al. establish that PDAC causes new-onset diabetes through unknown mechanisms, demonstrating the bidirectional relationship between PDAC and diabetes.

Constitutional 3

Abdominal Pain HP:0002027

Show evidence (2 references)

PMID:25726049 SUPPORT Other

"Common signs and symptoms of PDA include abdominal or back pain, jaundice, weight loss, pruritus, and nausea/vomiting."

The diagnostic review supports presentation but provides no numerical frequency denominator.

PMID:28785934 SUPPORT Human Clinical

"Preoperative pain does not predict the presence of perineural invasion or other pathologic prognostic factors in patients with resectable pancreatic adenocarcinoma."

Prospective 52-patient resectable cohort qualifies pain as a neural-invasion surrogate.

Fatigue HP:0012378

Back pain HP:0003418

Show evidence (1 reference)

PMID:25726049 SUPPORT Other

"Common signs and symptoms of PDA include abdominal or back pain, jaundice, weight loss, pruritus, and nausea/vomiting."

The diagnostic review supports presentation but provides no numerical frequency denominator.

Growth 1

Weight Loss HP:0001824

Show evidence (1 reference)

PMID:25726049 SUPPORT Other

"Common signs and symptoms of PDA include abdominal or back pain, jaundice, weight loss, pruritus, and nausea/vomiting."

The diagnostic review supports presentation but provides no numerical frequency denominator.

🧬

Genetic Associations

KRAS (Somatic Gain-of-Function Mutation)

Gene: KRAS hgnc:6407 gene page

Somatic

Show evidence (2 references)

PMID:33347393 SUPPORT Human Clinical

"This systematic review and meta-analysis supports the use of driver mutations in the P53, SMAD4, and KRAS genes as prognostic markers for pancreatic cancer."

Directly supports KRAS as an established driver mutation and prognostic marker in pancreatic cancer.

DOI:10.3389/fmed.2024.1369136 SUPPORT Other

"In the case of pancreatic ductal adenocarcinomas (PDAC), 90–92% harbor mutations in the oncogene KRAS, triggering canonical MAPK signaling."

Review-level estimate and signaling background; precise frequencies vary by assay and cohort.

TP53 (Somatic Loss-of-Function Mutation)

Gene: TP53 hgnc:11998 gene page

Somatic

Show evidence (1 reference)

PMID:37404765 SUPPORT Human Clinical

"the KRAS mutated group had a significantly higher percentage of TP53 (mutated vs wild-type: 80.2% vs 47.6%, p <0.0001)"

Foundation Medicine genomic profiling of 9,444 advanced PDAC cases showed TP53 mutations in 80.2% of KRAS-mutated PDAC.

SMAD4 (Somatic Loss-of-Function Mutation)

Gene: SMAD4 hgnc:6770 gene page

Somatic

Show evidence (1 reference)

PMID:37404765 SUPPORT Human Clinical

"SMAD4 (mutated vs wild-type: 26.8% vs 15.7%, p <0.0001)"

The clinical profiling cohort reports SMAD4 alteration rates by KRAS stratum; it does not explain differences between assays.

CDKN2A (Somatic Loss-of-Function Mutation)

Gene: CDKN2A hgnc:1787 gene page

Somatic

Show evidence (2 references)

PMID:18772397 SUPPORT Human Clinical

"This list includes the classic tumor suppressor genes CDKN2A (p16), SMAD4, and TP53, as well as genes that had not previously been implicated in pancreatic cancer development."

Directly identifies CDKN2A/p16 as a classic tumor suppressor gene affected by homozygous deletion in pancreatic cancers.

PMID:37404765 SUPPORT Human Clinical

"CDKN2A (mutated vs wild-type: 56.2% vs 34.4%, p <0.0001)"

Clinical profiling reports different CDKN2A alteration rates between KRAS strata; it does not quantify promoter silencing.

BRCA2 (Inherited predisposition and somatic homologous-recombination deficiency)

Gene: BRCA2 hgnc:1101 gene page

Autosomal dominant

Show evidence (1 reference)

PMID:31157963 SUPPORT Human Clinical

"Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population."

The POLO trial confirmed that BRCA-mutated PDAC patients represent a distinct subgroup that responds to PARP inhibition, validating the clinical relevance of BRCA2 mutations in PDAC.

BRCA1 (Inherited susceptibility)

Gene: BRCA1 hgnc:1100 gene page

Autosomal dominant

Show evidence (1 reference)

PMID:29922827 SUPPORT Human Clinical

"BRCA1 (0.6% of cases and 0.2% of controls; OR, 2.58; 95% CI, 1.54-4.05)"

Case-control germline association in 3,030 pancreatic cancer cases supports inherited risk, not somatic prevalence.

ATM (Inherited susceptibility)

Gene: ATM hgnc:795 gene page

Autosomal dominant

Show evidence (1 reference)

PMID:29922827 SUPPORT Human Clinical

"ATM (2.3% of cases and 0.37% of controls; OR, 5.71; 95% CI, 4.38-7.33)"

Case-control germline association in 3,030 pancreatic cancer cases supports inherited risk, not somatic prevalence.

MLH1 (Inherited susceptibility)

Gene: MLH1 hgnc:7127 gene page

Autosomal dominant

Show evidence (1 reference)

PMID:29922827 SUPPORT Human Clinical

"MLH1 (0.13% of cases and 0.02% of controls; OR, 6.66; 95% CI, 1.94-17.53)"

Case-control germline association in 3,030 pancreatic cancer cases supports inherited risk, not somatic prevalence.

NRG1 Fusions (Somatic oncogenic fusion)

Gene: NRG1 hgnc:7997 gene page

Somatic

Show evidence (1 reference)

PMID:39908431 SUPPORT Human Clinical

"Neuregulin 1 (NRG1) fusions are recurrent oncogenic drivers found in multiple solid tumors."

Primary clinical report describes the fusion-defined molecular treatment subset.

💊

Medical Actions

Surgical Resection

Action: Pancreatectomy NCIT:C15294

Resection offers potential long-term disease control in appropriately selected localized PDAC. Pancreaticoduodenectomy treats head lesions; distal pancreatectomy treats body/tail lesions. Multidisciplinary staging and perioperative or postoperative systemic therapy determine management.

Show evidence (1 reference)

PMID:28129987 SUPPORT Human Clinical

"Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection)."

The ESPAC-4 trial enrolled patients who underwent complete macroscopic resection for PDAC, confirming surgical resection as a standard treatment approach with adjuvant chemotherapy improving outcomes.

FOLFIRINOX Chemotherapy

Action: chemotherapy Ontology label: Chemotherapy NCIT:C15632 Regimen: modified FOLFIRINOX regimen Ontology label: Folfirinox Regimen NCIT:C11764

Agent: fluorouracil CHEBI:46345 leucovorin NCIT:C71631 irinotecan CHEBI:80630 oxaliplatin CHEBI:31941

Combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin. Used as first-line treatment for metastatic PDAC in fit patients and as adjuvant therapy after surgical resection. Provides superior survival compared to gemcitabine alone but with greater toxicity.

Show evidence (2 references)

PMID:30575490 SUPPORT Human Clinical

"Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects."

The PRODIGE 24 trial demonstrated that adjuvant modified FOLFIRINOX significantly improved disease-free and overall survival compared to gemcitabine in resected PDAC patients.

PMID:21561347 SUPPORT Human Clinical

"The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group"

Randomized metastatic trial in patients with ECOG performance status 0 or 1 supports first-line use in fit patients, separately from the adjuvant trial.

Gemcitabine-Based Chemotherapy

Action: chemotherapy Ontology label: Chemotherapy NCIT:C15632

Agent: gemcitabine CHEBI:175901 nab-paclitaxel NCIT:C2688

Gemcitabine with nab-paclitaxel improves survival over gemcitabine alone in metastatic PDAC, with increased neuropathy and myelosuppression. Regimen selection depends on fitness and prior therapy; separate trials do not establish superior tolerability to FOLFIRINOX.

Show evidence (1 reference)

PMID:24131140 SUPPORT Human Clinical

"nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased."

The Von Hoff et al. phase 3 trial demonstrated that nab-paclitaxel plus gemcitabine significantly improved overall survival (8.5 vs 6.7 months) in metastatic pancreatic adenocarcinoma.

PARP Inhibitor Therapy

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Maintenance olaparib improves progression-free survival in metastatic PDAC with germline BRCA1/2 pathogenic variants and no progression after at least 16 weeks of first-line platinum chemotherapy. POLO did not show a statistically significant overall-survival benefit in the final analysis. This evidence does not extend automatically to every DNA-repair alteration.

Show evidence (3 references)

DOI:10.1200/jco.21.01604 SUPPORT Human Clinical

"The phase III POLO study demonstrated significant progression-free survival (PFS) benefit for active olaparib maintenance therapy versus placebo for patients with metastatic pancreatic adenocarcinoma and a germline BRCA mutation."

The phase III POLO trial supports maintenance olaparib in germline BRCA-mutated metastatic pancreatic adenocarcinoma; folded in from the former Metastatic_Pancreatic_Adenocarcinoma entry.

PMID:31157963 SUPPORT Human Clinical

"We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy."

The POLO trial demonstrated that maintenance olaparib significantly prolonged progression-free survival in germline BRCA-mutated metastatic pancreatic cancer patients who had not progressed on platinum-based chemotherapy.

DOI:10.1200/jco.21.01604 SUPPORT Human Clinical

"No statistically significant OS benefit was observed (median 19.0 v 19.2 months; hazard ratio [HR], 0.83; 95% CI, 0.56 to 1.22; P = .3487)."

Final POLO analysis qualifies the PFS benefit with the nonsignificant OS comparison.

Daraxonrasib (RAS(ON) Multiselective Inhibitor)

Action: Pharmacotherapy NCIT:C15986

Agent: daraxonrasib CHEBI:746946

Platform: Small molecule

Daraxonrasib is a cyclophilin-A-dependent inhibitor of active GTP-bound mutant and wild-type RAS. In phase III RASolute 302 for previously treated metastatic PDAC, median overall survival was 13.2 versus 6.6 months in the RAS G12 population (hazard ratio 0.40); median progression-free survival was 7.3 versus 3.5 months. These clinical outcomes establish treatment efficacy, not a universal resistance mechanism or an immune basis for survival benefit.

Mechanism Target:

INHIBITS KRAS Oncogene Activation — Daraxonrasib directly inhibits the active RAS(ON) state produced by oncogenic KRAS codon-12 mutations, the initiating driver of PDAC, suppressing constitutive RAS-MAPK signaling.

Show evidence (1 reference)

PMID:42223072 SUPPORT Human Clinical

"Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of the active guanosine triphosphate-bound state of mutant and wild-type RAS."

The RASolute 302 report describes daraxonrasib's mechanism as direct inhibition of the active GTP-bound RAS state driven by mutant KRAS in PDAC.

ACTIVATES Immunosuppressive TME Reversibility under RAS(ON) Inhibition — Preclinical PDAC immune remodeling follows RAS inhibition; this is not an inferred immune mechanism for the phase III survival effect.

Show evidence (1 reference)

PMID:40057911 SUPPORT Model Organism

Direct PDAC evidence was omitted from the immune report despite being cited in the resistance report.

ACTIVATES Regulatory T-Cell Recruitment after KRAS Inhibition — Treg recruitment is a model-dependent adaptation documented with daraxonrasib and MRTX1133.

Show evidence (1 reference)

DOI:10.1038/s41467-026-75960-3 SUPPORT Model Organism

Newer mouse PDAC evidence replaces the unsupported positive Treg-relief node.

Show evidence (3 references)

clinicaltrials:NCT06625320 SUPPORT Human Clinical

"The purpose of this study is to evaluate the safety and efficacy of a novel RAS(ON) inhibitor compared to standard(s) of care (SOC) treatment."

ClinicalTrials.gov documents RASolute 302 as a phase 3 evaluation of the RAS(ON) inhibitor daraxonrasib versus standard-of-care chemotherapy in previously treated metastatic PDAC.

PMID:42223072 SUPPORT Human Clinical

"Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of the active guanosine triphosphate-bound state of mutant and wild-type RAS."

Establishes daraxonrasib's mechanism of action as a RAS(ON) multiselective tri-complex inhibitor of the active GTP-bound state of mutant and wild-type RAS, the basis for its target_mechanisms link to KRAS-centered signaling.

PMID:42223072 SUPPORT Human Clinical

"The median overall survival in the RAS G12 population was 13.2 months with daraxonrasib and 6.6 months with chemotherapy, and the median overall survival in the overall population was 13.2 months and 6.7 months, respectively; the hazard ratio was 0.40 in both populations (P<0.001)."

RASolute 302 demonstrated a significant overall survival benefit for daraxonrasib over chemotherapy (hazard ratio for death 0.40) in previously treated metastatic PDAC.

Experimental Mutant KRAS Vaccine for Residual Disease

Action: vaccination Ontology label: Vaccination NCIT:C15346

Platform: Vaccine

The phase I AMPLIFY-201 trial evaluated ELI-002 2P, an amphiphile G12D/G12R KRAS peptide vaccine plus CpG adjuvant, in patients with molecular residual KRAS-mutated pancreatic or colorectal cancer. It induced KRAS-specific T-cell responses. This early mixed-cancer study does not establish prevention in healthy high-risk individuals or randomized recurrence/survival benefit.

Show evidence (1 reference)

PMID:38195752 SUPPORT Human Clinical

"Cancer vaccine ELI-002 2P enhances lymph node delivery and immune response using amphiphile (Amph) modification of G12D and G12R mutant KRAS (mKRAS) peptides (Amph-Peptides-2P) together with CpG oligonucleotide adjuvant (Amph-CpG-7909)."

Describes the mutant-KRAS amphiphile vaccine platform evaluated in the phase 1 AMPLIFY-201 trial.

Experimental KRAS Inhibition with Immune Checkpoint Blockade

Action: Immunotherapy NCIT:C15262

Checkpoint combinations with RAS inhibitors are supported by mouse PDAC experiments. RMC-7977/daraxonrasib plus PD-1-based therapy worked in one study, whereas a later study found CTLA-4 blockade specifically effective and associated with Treg reprogramming and tertiary lymphoid structures. Regimen, model, timing and checkpoint partner matter. These results do not establish routine clinical daraxonrasib-checkpoint treatment.

Mechanism Target:

ACTIVATES Immunosuppressive TME Reversibility under RAS(ON) Inhibition — Experimental combinations deepen immune-dependent tumor control.

Show evidence (1 reference)

PMID:40057911 SUPPORT Model Organism

"the combination of RAS(ON) multi-selective inhibitors with immunotherapy conferred deeper and more durable tumor regressions, including complete responses not seen with either treatment alone."

Direct immunocompetent PDAC combination evidence.

Show evidence (1 reference)

DOI:10.1038/s41467-026-75960-3 SUPPORT Model Organism

"Kras* inhibition induces T-cell influx and offers a therapeutic window to specifically prime PDAC to anti-CTLA4 immune checkpoint blockade efficacy, in contrast to anti-PD1, anti-Tim3, anti-Lag3, anti-Vista, and anti-4-1BB agonist combination therapy."

The newer model-specific comparison qualifies general checkpoint synergy.

NALIRIFOX

Action: Chemotherapy NCIT:C15632

Agent: liposomal irinotecan NCIT:C82676 5-fluorouracil CHEBI:46345 leucovorin CHEBI:748997 oxaliplatin CHEBI:31941

Platform: Small molecule Delivery: Liposome

Only the irinotecan component is carried in a liposome; the oxaliplatin, fluorouracil and leucovorin in this regimen are conventional formulations. The carrier is what separates NALIRIFOX from FOLFIRINOX, which delivers free irinotecan, so it is part of the regimen's identity rather than a formulation footnote. No targeting ligand: a PEGylated liposome accumulates passively.

Liposomal irinotecan, oxaliplatin, fluorouracil and leucovorin is a first-line option for fit patients with metastatic PDAC. NAPOLI 3 improved median overall survival to 11.1 versus 9.2 months compared with gemcitabine-nab-paclitaxel; high-grade toxicity was frequent in both groups.

Show evidence (1 reference)

PMID:37708904 SUPPORT Human Clinical

"Median overall survival was 11·1 months (95% CI 10·0-12·1) with NALIRIFOX versus 9·2 months (8·3-10·6) with nab-paclitaxel-gemcitabine"

Randomized phase III evidence supports this contemporary chemotherapy option.

Zenocutuzumab for NRG1 Fusion-Positive Disease

Action: Targeted Therapy NCIT:C93352

Agent: zenocutuzumab CHEBI:757449

Platform: Monoclonal antibody

The HER2/HER3 bispecific antibody targets the NRG1-fusion signaling subset. In the phase II eNRGy trial, 15 of 36 evaluable pancreatic-cancer patients responded (42%); this single-arm molecularly selected result does not describe unselected PDAC.

Show evidence (1 reference)

PMID:39908431 SUPPORT Human Clinical

"15 of 36 patients (42%; 95% CI, 25 to 59) with pancreatic cancer"

Pancreatic-cancer subgroup response in the NRG1-fusion-selected eNRGy trial.

Checkpoint Inhibition for MSI-High or Mismatch-Repair-Deficient Disease

Action: Immunotherapy NCIT:C15262

Agent: pembrolizumab NCIT:C106432

Platform: Monoclonal antibody

Mismatch-repair deficiency or high microsatellite instability identifies a small immune-treatment-sensitive subset. Responses in selected case series should not be generalized to microsatellite-stable PDAC or used as a population-wide response estimate. Pembrolizumab was used in eight of the nine immunotherapy-treated patients in the cited series; one received ipilimumab plus nivolumab, so the pooled response rate is not a pembrolizumab-only estimate.

Show evidence (2 references)

DOI:10.1136/jitc-2021-004485 SUPPORT Human Clinical

"The overall response rate by Response Evaluation Criteria in Solid Tumors was 77% (7/9)."

A retrospective nine-patient MSI-high advanced pancreatic-cancer series supports subset activity; the small selected denominator limits precision.

DOI:10.1136/jitc-2021-004485 SUPPORT Human Clinical

"Eight out of nine patients received single-agent pembrolizumab (8/9), while one received ipilimumab plus nivolumab."

The agent binding identifies the predominant treatment in this small retrospective series; the nine-patient outcome includes one different checkpoint regimen.

Nutritional Support

Action: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Assess weight loss and dietary intake and provide individualized nutritional counseling and oral supplementation. Nutritional support complements treatment of exocrine insufficiency; it is not itself pancreatic enzyme replacement.

Show evidence (1 reference)

PMID:32631175 SUPPORT Other

"Improving the nutritional status, either with parenteral nutrition or oral supplementation, can increase the body weight, skeletal muscle mass, fat mass and quality of life, facilitating the administration of chemotherapy without interruption."

The review background supports nutritional supplementation as supportive care. This entry concerns dietary counseling and oral support; parenteral nutrition is a separate medical route and is not represented by the BEHAVIORAL modality.

Pancreatic Enzyme Replacement

Action: Supportive Care NCIT:C15747

Agent: pancrelipase CHEBI:753090

Platform: Protein replacement

Pancreatic enzyme replacement, including pancrelipase, is used for exocrine insufficiency and maldigestion when indicated. Mixed observational/trial pooled survival associations do not establish a causal survival benefit; an 88-patient randomized trial of pancrelipase in unresectable pancreatic cancer did not improve the primary eight-week BMI endpoint.

Mechanism Target:

BYPASSES Exocrine Pancreatic Insufficiency — Oral enzyme replacement supplies digestive enzymes to compensate for inadequate endogenous pancreatic enzyme delivery; it does not restore destroyed pancreatic tissue.

Show evidence (1 reference)

PMID:32631175 SUPPORT Other

"Pancreatic enzyme replacement therapy (PERT) is the standard treatment for PEI."

The review describes symptomatic enzyme replacement for exocrine insufficiency, independently of uncertain survival benefit.

Show evidence (3 references)

PMID:32631175 SUPPORT Human Clinical

"The pooled prevalence of pancreatic exocrine insufficiency in advanced pancreatic cancer was 72% (95% confidence interval: 55-86%)"

Meta-analysis supports substantial exocrine insufficiency specifically in advanced pancreatic cancer; heterogeneity and tumor location limit generalization to all PDAC.

PMID:29851751 SUPPORT Human Clinical

"Patients with unresectable PC receiving chemotherapy were randomly assigned to pancrelipase and nonpancrelipase groups."

The randomized trial establishes the specific enzyme preparation used in this pancreatic-cancer population.

PMID:29851751 SUPPORT Human Clinical

"In this randomized controlled trial, pancrelipase failed to improve the change in BMI at 8 weeks in PC patients receiving chemotherapy."

The null primary endpoint prevents presenting enzyme replacement as a proven general weight-gain or survival treatment; clinical use for exocrine insufficiency is a separate indication.

Biliary Drainage

Action: Supportive Care NCIT:C15747

Platform: Surgery

Endoscopic placement of a fully covered self-expandable metallic biliary stent can relieve malignant biliary obstruction. Select procedural drainage according to anatomy, symptoms and the clinical treatment plan.

Mechanism Target:

BYPASSES Obstructive Jaundice — Biliary stenting bypasses the obstructed segment and restores drainage in patients with malignant biliary obstruction.

Show evidence (1 reference)

PMID:41067164 SUPPORT Other

"In the event of biliary obstruction, endoscopic placement of a fully covered, self-expandable metallic biliary stent is suggested"

Guideline addresses biliary obstruction.

Show evidence (1 reference)

PMID:41067164 SUPPORT Other

"In the event of biliary obstruction, endoscopic placement of a fully covered, self-expandable metallic biliary stent is suggested"

Guideline addresses biliary obstruction.

Pain Management

Action: Supportive Care NCIT:C15747

Platform: Other

Provide individualized pain assessment and specialist-guided multimodal analgesia alongside cancer-directed therapy. This supportive-care category spans medication and procedural approaches, so it does not designate one pharmacologic platform or a single therapeutic agent.

Show evidence (1 reference)

PMID:41067164 SUPPORT Other

"Effective pain control is strongly recommended and should involve a pain control specialist when required"

Guideline supports active specialist pain management.

Experimental RAS-EGFR-STAT3 Combination

Action: Targeted Therapy NCIT:C93352

Agent: daraxonrasib CHEBI:746946 afatinib CHEBI:61390 SD36 NCIT:C200712

Platform: Small molecule

Daraxonrasib, afatinib and the STAT3 degrader SD36 produced prolonged regressions in orthotopic, genetically engineered and patient-derived xenograft PDAC models. This corrected primary study also tested genetic RAF1/EGFR/STAT3 ablation. It supports combination research, not routine patient treatment or proof that immunity is irrelevant.

Mechanism Target:

INHIBITS KRAS Oncogene Activation — Daraxonrasib inhibits active RAS within the experimental daraxonrasib-afatinib-SD36 combination. Linking the same treatment to RAS signaling and observed resistance prevention connects the experimental resistance branch without asserting that initiating KRAS activation causes acquired amplification in untreated tumors.

Show evidence (1 reference)

PMID:42224594 SUPPORT Model Organism

"a combination of selective inhibitors of KRAS (RMC-6236/daraxonrasib), EGFR family (afatinib), and STAT3 (SD36) induced the complete regression of orthotopic PDAC tumors with no evidence of tumor resistance for over 200 d posttreatment."

The corrected mouse-model study identifies daraxonrasib as the KRAS/RAS-directed component of the combination. This pharmacologic target link does not establish acquired amplification as a consequence of the initiating mutation or identify a human resistance frequency.

INHIBITS Acquired RAS(ON) Inhibitor Resistance — Experimental multilevel pathway inhibition delayed or prevented detected resistance within the studied follow-up.

Show evidence (1 reference)

PMID:42224594 SUPPORT Model Organism

Corrected republication supports pharmacologic mouse-model durability; no human efficacy or permanent cure is established.

Show evidence (1 reference)

PMID:42224594 SUPPORT Model Organism

Corrected republication supports pharmacologic mouse-model durability; no human efficacy or permanent cure is established.

🌍

Environmental Factors

Tobacco Smoking

Tobacco use is an established modifiable pancreatic-cancer risk factor. The cited aggregate pancreatic-disease risk ratio is not a PDAC-specific estimate and does not establish a causal route through KRAS mutation.

Show evidence (2 references)

PMID:34002083 SUPPORT Human Clinical

"there are key modifiable risk factors for pancreatic cancer such as cigarette smoking, obesity, diabetes and alcohol intake."

Directly identifies cigarette smoking as a leading modifiable risk factor for pancreatic cancer.

PMID:24509242 SUPPORT Human Clinical

"Current tobacco use was the single most important risk factor for pancreatic diseases (RR, 1.87; 95% CI, 1.54-2.27)"

Meta-analysis of 51 population-based prospective cohort studies identified tobacco use as the single most important modifiable risk factor for pancreatic diseases with an RR of 1.87. The outcome measured is pancreatic diseases as a class, and the same abstract reports that tobacco has a bigger effect on acute and chronic pancreatitis than on pancreatic cancer, so this figure is not a cancer-specific estimate.

Obesity

Obesity associates with pancreatic disease and is addressed in pancreatic-cancer prevention guidance. The cited pooled pancreatic-disease estimate is not specific to PDAC and does not isolate diet or a molecular route.

Show evidence (1 reference)

PMID:24509242 SUPPORT Human Clinical

"followed by obesity (RR, 1.48; 95% CI, 1.15-1.92)"

Meta-analysis of prospective cohort studies identified obesity as the second most important risk factor for pancreatic diseases with an RR of 1.48.

🔬

Biochemical Markers

CA 19-9

Show evidence (1 reference)

PMID:23331006 SUPPORT Human Clinical

"In 57 studies involving 3,285 pancreatic carcinoma cases, the combined sensitivity of CA 19-9 was 78.2% and in 37 studies involving 1,882 cases with benign pancreatic disease the specificity of CA 19-9 was 82.8%."

Poruk et al. meta-analysis established CA 19-9 sensitivity of 78.2% and specificity of 82.8% for pancreatic carcinoma diagnosis.

Carcinoembryonic Antigen (CEA)

Show evidence (1 reference)

PMID:23331006 SUPPORT Human Clinical

"From the combined analysis of studies reporting CEA, the sensitivity was 44.2% (1,324 cases) and the specificity was 84.8% (656 cases)."

Poruk et al. meta-analysis showed CEA has lower sensitivity (44.2%) than CA 19-9 but comparable specificity (84.8%) for pancreatic carcinoma.

🔬

Diagnosis

Pancreatic-Protocol Cross-Sectional Imaging

Multiphasic contrast-enhanced CT establishes lesion anatomy, vascular involvement and metastatic extent. MRI is an alternative or problem-solving examination; resectability requires multidisciplinary interpretation.

Show evidence (1 reference)

PMID:41067164 SUPPORT Other

"Multiphasic contrast-enhanced thoracic-abdominal and pelvic CT, including late arterial phase and portal venous phase, should be used as the first-line imaging modality for suspected pancreatic cancer"

Defines first-line diagnostic imaging.

Tissue Diagnosis

Cytology or biopsy, preferably by endoscopic-ultrasound guidance where appropriate, confirms malignancy before systemic therapy. Tissue morphology and clinical imaging must be reconciled with the differential diagnosis.

Show evidence (1 reference)

PMID:41067164 SUPPORT Other

"Cytology or biopsy proof of pancreatic cancer should be obtained before initiation of ChT in localised disease, preferably by EUS guidance"

Specifies tissue confirmation before chemotherapy.

Germline and Tumor Molecular Testing

Inherited susceptibility testing and tumor profiling identify clinically relevant BRCA, mismatch-repair and other actionable alterations. KRAS-wild-type tumors particularly warrant a search for alternative drivers, including fusions; the result must match the treatment-specific evidence.

Show evidence (1 reference)

PMID:41067164 SUPPORT Other

"BRCA genetic testing should be offered to all patients with metastatic pancreatic cancer"

Supports germline testing in metastatic disease.

🪜

Stages

Resectable

Localized disease judged technically resectable by multidisciplinary pancreatic-protocol imaging and clinical assessment. Pancreaticoduodenectomy or distal pancreatectomy is selected by location; postoperative systemic therapy is standard for suitable patients.

Borderline Resectable

Localized disease with a high risk of margin-positive resection, commonly related to vascular involvement. Induction therapy and reassessment guide consideration of surgery.

Show evidence (1 reference)

PMID:41067164 SUPPORT Other

"Patients with borderline resectable pancreatic cancer have a high probability of an R1 resection and should be considered for induction treatment"

Consensus recommendation links borderline resectability to margin risk and induction treatment.

Locally Advanced

Nonmetastatic disease with local involvement precluding upfront resection. Systemic treatment, symptom care and reassessment for selected local approaches are appropriate.

Metastatic

Distant spread, commonly to liver, peritoneum or lung, requires systemic and supportive care. The metastasis, RAS-inhibitor resistance and immune-remodeling mechanisms belong to this PDAC model rather than a separate disease.

📊

Related Datasets

Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas geo:GSE111672

Multimodal PDAC dataset combining spatial transcriptomics and single-cell RNA-seq from primary pancreatic tumors. Useful for resolving how malignant ductal cells, macrophages, dendritic cells, and fibroblast states are spatially organized within the tumor microenvironment.

human MULTI OMICS n=23

pancreatic tumor tissue UBERON:0001264

Conditions: primary pancreatic ductal adenocarcinoma

PMID:31932730

GEO has 23 sample records derived from six patients with single-cell and spatial measurements. Assay/sample count is not the number of independent patient tumors. Spatial colocalization supports ecological hypotheses but not causal cell-cell signaling.

Single-cell transcriptomics analysis of pancreatic primary tumor and metastatic biopsy tissues geo:GSE154778

Single-cell RNA-seq of 10 pancreatic primary tumors and 6 metastatic biopsies. Captures tumor, stromal, and immune programs across primary and metastatic disease, making it useful for modeling dissemination and metastatic niche adaptation in PDAC.

human SINGLE CELL RNA SEQ n=16

pancreatic tumor tissue UBERON:0001264

Conditions: primary pancreatic ductal adenocarcinoma metastatic pancreatic ductal adenocarcinoma

PMID:32988401

GEO reports 10 primary tumors and 6 metastatic lesion biopsies profiled on the 10x Genomics Chromium platform. High-value bridge dataset between primary-tumor ecology and metastatic evolution.

Multimodal Mapping of the Tumor and Peripheral Blood Immune Landscape in Human Pancreatic Cancer geo:GSE155698

Single-cell immune-focused PDAC resource spanning tumor tissue, adjacent normal pancreas, and peripheral blood mononuclear cells from pancreatic cancer patients, plus healthy-donor PBMC controls. Especially useful for linking the local TME to the systemic macroenvironment.

human SINGLE CELL RNA SEQ n=41

pancreatic tumor tissue UBERON:0001264 adjacent normal pancreatic tissue UBERON:0001264 peripheral blood UBERON:0000178

Conditions: pancreatic ductal adenocarcinoma tumor tissue adjacent normal pancreas pancreatic cancer patient PBMCs healthy donor PBMCs

PMID:34296197

Live GEO metadata lists 41 sample records, while the submitted design describes 16 tumor, 3 adjacent normal, 16 patient PBMC and 4 healthy PBMC samples (39 total). The discrepancy is preserved explicitly; reconcile the GSM-level manifest before cohort analysis and do not equate sample records with independent patients. Raw data are described as deposited in dbGaP phs002071.v1.p1; this review did not access controlled individual data.

Microarray gene-expression profiles of 69 pancreatic tumors and 61 adjacent non-tumor tissue from patients with pancreatic ductal adenocarcinoma geo:GSE62452

Large paired bulk expression cohort of PDAC tumors and adjacent non-tumor tissue. Useful as a broader transcriptomic reference set for tumor-versus-normal contrasts and for anchoring subtype-level or pathway-level signatures in a larger patient cohort.

human MICROARRAY n=130

pancreatic tumor tissue UBERON:0001264

Conditions: pancreatic ductal adenocarcinoma tumor tissue adjacent non-tumor pancreatic tissue

PMID:27197190

GEO reports 69 pancreatic tumors and 61 adjacent non-tumor tissues, with earlier Affymetrix data from GSE28735 incorporated into the merged normalized cohort. Useful as a bulk-expression complement to the single-cell and spatial resources above.

🔬

Clinical Trials

NCT06625320 PHASE_III

RASolute 302: a phase 3, international, open-label, randomized trial comparing daraxonrasib (RMC-6236) with the investigator's choice of standard chemotherapy in patients with previously treated metastatic PDAC. The trial met its dual primary endpoints of overall survival and progression-free survival in the RAS G12 population.

Target Phenotypes: Neoplasm of the pancreas HP:0002894

Show evidence (2 references)

clinicaltrials:NCT06625320 SUPPORT Human Clinical

"The purpose of this study is to evaluate the safety and efficacy of a novel RAS(ON) inhibitor compared to standard(s) of care (SOC) treatment."

ClinicalTrials.gov confirms RASolute 302 (NCT06625320) evaluated the RAS(ON) inhibitor daraxonrasib against standard-of-care chemotherapy in mPDAC.

PMID:42223072 SUPPORT Human Clinical

"Among patients with previously treated mPDAC, treatment with daraxonrasib led to significantly longer overall survival and progression-free survival than chemotherapy."

The primary-results publication reports that RASolute 302 met its overall survival and progression-free survival endpoints favoring daraxonrasib.

NCT04083235 PHASE_III

NAPOLI 3 randomized first-line NALIRIFOX against gemcitabine-nab-paclitaxel in metastatic pancreatic ductal adenocarcinoma.

Show evidence (1 reference)

PMID:37708904 SUPPORT Human Clinical

"Median overall survival was 11·1 months (95% CI 10·0-12·1) with NALIRIFOX versus 9·2 months (8·3-10·6) with nab-paclitaxel-gemcitabine"

Published randomized trial provides the outcome; no live recruitment-status claim is inferred.

NCT02184195 PHASE_III

POLO randomized maintenance olaparib versus placebo in germline BRCA1/2 metastatic pancreatic cancer without progression on first-line platinum; PFS improved but final OS was not statistically different.

Show evidence (3 references)

DOI:10.1200/jco.21.01604 SUPPORT Human Clinical

The phase III POLO trial supports maintenance olaparib in germline BRCA-mutated metastatic pancreatic adenocarcinoma; folded in from the former Metastatic_Pancreatic_Adenocarcinoma entry.

PMID:31157963 SUPPORT Human Clinical

DOI:10.1200/jco.21.01604 SUPPORT Human Clinical

"No statistically significant OS benefit was observed (median 19.0 v 19.2 months; hazard ratio [HR], 0.83; 95% CI, 0.56 to 1.22; P = .3487)."

Final POLO analysis qualifies the PFS benefit with the nonsignificant OS comparison.

NCT02715804 PHASE_III

HALO 109-301 compared PEGPH20 plus gemcitabine-nab-paclitaxel with placebo plus chemotherapy in hyaluronan-high metastatic PDAC. Increased response rate did not improve survival, limiting clinical translation of stromal hyaluronan depletion.

Show evidence (1 reference)

PMID:32706635 SUPPORT Human Clinical

"The addition of PEGPH20 to AG increased the ORR but did not improve OS or PFS."

Randomized trial limits extrapolation from preclinical matrix/hypoperfusion rescue to clinical survival.

🧫

Experimental Models

Human PDAC Cell and Organoid RAS-Response Models ORGANOID

Patient-derived PDAC organoids and established cell models permit driver-specific RMC-7977 sensitivity assays; engineered and selected cell models test bypass mechanisms. These isolated epithelial systems do not reproduce the complete immune or desmoplastic microenvironment.

Publication

PMID:38588697

Pathograph links

KRAS Oncogene Activation perturbs Tests RAS-GTP-inhibitor signaling and growth response.

Limitations: Cell viability and target phosphorylation are not patient response or immune-remodeling endpoints.

Show evidence (1 reference)

PMID:38588697 SUPPORT In Vitro

"RMC-7977 exhibited low nanomolar potency on the viability of most human and mouse PDAC cell lines and human PDAC organoids"

Direct cell and organoid assays establish activity with subtype/driver variation, not whole-organism immunity.

🐁

Animal Models

Immunocompetent Mouse PDAC RAS-Inhibition Models

RMC-7977 and daraxonrasib experiments test tumor regression, immune-cell changes and immunotherapy combinations in immunocompetent PDAC. Results depend on regimen and tumor/host model and do not establish patient immune pharmacodynamics.

Species

Mouse

Genotype

KRAS-driven autochthonous and syngeneic PDAC systems

Publication

PMID:40057911

Pathograph links

Immunosuppressive TME Reversibility under RAS(ON) Inhibition perturbs Measures immune remodeling and depletion-defined immune contribution.

Limitations: Mouse immune ecosystems and drug exposures differ from human metastatic disease.

Show evidence (1 reference)

PMID:40057911 SUPPORT Model Organism

Direct PDAC evidence was omitted from the immune report despite being cited in the resistance report.

KPC RMC-7977 Acquired-Resistance Models

Chronic RMC-7977 exposure produces initially responding and subsequently relapsing KPC tumors. MYC and YAP/TEAD programs were interrogated; tool-compound models and clinical daraxonrasib cohorts have different resistance distributions.

Species

Mouse

Genotype

Kras/Trp53-driven genetically engineered pancreatic cancer

Publication

PMID:38588697

Pathograph links

MYC Amplification-Driven RAS-Independent Proliferation perturbs Tracks relapse-associated MYC amplification and downstream bypass.

Limitations: Selected mouse tumors do not estimate patient route prevalence.

Show evidence (1 reference)

PMID:38588697 SUPPORT Model Organism

"Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro."

Primary 2024 RMC-7977 study supplies stronger support than the systematic review cited by OpenScientist.

🧮

Computational Models

PDAC CAF-Mediated Invasion PhysiCell Model C++/XML/CSV PhysiCell AGENT_BASED

Grammar-based PhysiCell agent-based model of pancreatic ductal adenocarcinoma neoplastic cells and cancer-associated fibroblasts. The model encodes fibroblast-mediated invasion, epithelial-mesenchymal state switching, and ECM-dependent motility tradeoffs using human-interpretable cell rules informed by PDAC spatial transcriptomics and coculture data.

Repository ↗ DOI:10.1016/j.cell.2025.06.048 Base model: PhysiCell grammar manuscript release DOI:10.5281/zenodo.16285252

Variable	Model ID	Unit	Ontology Mappings
inflammatory_signal Generic inflammatory signaling field used to bias migration and mesenchymal-to-epithelial state transitions.	`inflammatory_signal`	dimensionless field
ecm Extracellular-matrix density field driving stromal invasion and epithelial-mesenchymal plasticity.	`ecm`	dimensionless field	Extracellular matrix
epithelial_normal_cells Abundance of non-malignant epithelial agents in the coculture invasion simulation.	`epithelial_normal`	cells	epithelial cell
mesenchymal_normal_cells Abundance of non-malignant mesenchymal-state agents in the invasion simulation.	`mesenchymal_normal`	cells	mesenchymal cell
fibroblast_cells Abundance of fibroblast / CAF-like agents in the invasion simulation.	`fibroblast`	cells	fibroblast
epithelial_tumor_cells Abundance of epithelial-state malignant agents in the invasion simulation.	`epithelial_tumor`	cells	epithelial tumor cell
mesenchymal_tumor_cells Abundance of mesenchymal-state malignant agents in the invasion simulation.	`mesenchymal_tumor`	cells	mesenchymal tumor cell

Pathograph links

Desmoplastic Stroma Implements ECM-driven fibroblast motility and epithelial-mesenchymal state switching encoded in `config/cell_rules.csv` for the stromal invasion program.

Findings

ECM increases epithelial-to-mesenchymal switching of tumor epithelial cells in the executable PDAC invasion model.

"epithelial_tumor,ecm,increases,transform to mesenchymal_tumor,0.01,0.01,4,0"

Fibroblast migration is explicitly controlled by ECM-dependent rules in the invasion model.

"fibroblast,ecm,increases,migration speed,3.470551875,9.999679617,1.153017946,0"

Notes

Manuscript-synced sample model from the official PhysiCell grammar_samples release. Relevant configs include `config/PhysiCell_settings_PDAC.xml`, the rule table in `config/cell_rules.csv`, and coculture initial conditions under `config/ics/`. The pinned v2.0.1 repository, XML configurations and rule tables were inspected in this review. This is a published computational model record; no simulation, calibration or patient-response validation was performed here, and it does not establish daraxonrasib immune or resistance predictions.

PDAC Immunotherapy PhysiCell Model C++/XML/CSV PhysiCell AGENT_BASED

Grammar-based PhysiCell agent-based PDAC tumor-immune model initialized from PDAC tissue compositions. The model simulates combination therapy with GVAX, nivolumab, and urelumab across heterogeneous baseline microenvironment states using explicit cell-state and interaction rules.

Repository ↗ DOI:10.1016/j.cell.2025.06.048 Base model: PhysiCell grammar manuscript release DOI:10.5281/zenodo.16285252

Variable	Model ID	Unit	Ontology Mappings
oxygen Diffusible oxygen field used to control tumor proliferation, macrophage polarization logic, and necrotic stress.	`oxygen`	substrate density	dioxygen
debris Extracellular dead-cell debris field that attracts macrophages and reflects local cell death burden.	`debris`	substrate density
pro_inflammatory_factor Generic pro-inflammatory signaling field that boosts T-cell attack and chemotaxis in the model.	`pro-inflammatory factor`	substrate density
anti_inflammatory_factor Generic anti-inflammatory signaling field that suppresses T-cell migration and attack in the model.	`anti-inflammatory factor`	substrate density
PD-L1lo_tumor_cells Abundance of PD-L1-low malignant epithelial agents in the PDAC immunotherapy simulation.	`PD-L1lo_tumor`	cells	epithelial tumor cell
PD-L1hi_tumor_cells Abundance of PD-L1-high malignant epithelial agents in the PDAC immunotherapy simulation.	`PD-L1hi_tumor`	cells	epithelial tumor cell Programmed cell death 1 ligand 1
macrophages Abundance of macrophage agents in the PDAC immunotherapy simulation.	`macrophage`	cells	macrophage
PD-1hi_CD137lo_CD8_T_cells Abundance of PD-1-high CD137-low CD8 T-cell agents in the PDAC immunotherapy simulation.	`PD-1hi_CD137lo_CD8_Tcell`	cells	PD-1-high CD137-low CD8 T cell
PD-1lo_CD137lo_CD8_T_cells Abundance of PD-1-low CD137-low CD8 T-cell agents in the PDAC immunotherapy simulation.	`PD-1lo_CD137lo_CD8_Tcell`	cells	PD-1-low CD137-low CD8 T cell
PD-1hi_CD137hi_CD8_T_cells Abundance of PD-1-high CD137-high CD8 T-cell agents in the PDAC immunotherapy simulation.	`PD-1hi_CD137hi_CD8_Tcell`	cells	PD-1-high CD137-high CD8 T cell
PD-1lo_CD137hi_CD8_T_cells Abundance of PD-1-low CD137-high CD8 T-cell agents in the PDAC immunotherapy simulation.	`PD-1lo_CD137hi_CD8_Tcell`	cells	PD-1-low CD137-high CD8 T cell
PD-1hi_CD4_T_cells Abundance of PD-1-high CD4 T-cell agents in the PDAC immunotherapy simulation.	`PD-1hi_CD4_Tcell`	cells	PD-1-high CD4 T cell
PD-1lo_CD4_T_cells Abundance of PD-1-low CD4 T-cell agents in the PDAC immunotherapy simulation.	`PD-1lo_CD4_Tcell`	cells	PD-1-low CD4 T cell

Pathograph links

Immune Evasion Encodes PD-L1-dependent suppression of T-cell motility and attack probabilities, plus macrophage inflammatory-state rules, in `config/cell_rules.csv`.

Findings

Contact with PD-L1-high tumor cells reduces CD8 T-cell migration in the executable PDAC immunotherapy model.

"PD-1lo_CD137lo_CD8_Tcell,contact with PD-L1hi_tumor,decreases,migration speed,0,0.1,2,0"

Anti-inflammatory signals decrease CD8 T-cell attack against tumor cells in the executable PDAC immunotherapy model.

"PD-1lo_CD137hi_CD8_Tcell,anti-inflammatory factor,decreases,attack PD-L1hi_tumor,0,2.5,2,0"

Macrophage oxygen sensing controls pro- versus anti-inflammatory factor secretion in the executable PDAC immunotherapy model.

"macrophage,oxygen,decreases,anti-inflammatory factor secretion,0,5,4,0"

Notes

Manuscript-synced sample model from the official PhysiCell grammar_samples release. Therapy-specific initial-condition files are stored in `config/ic_cells/`, and the core executable interaction logic is in `config/cell_rules.csv`. The pinned v2.0.1 repository, XML configurations and rule tables were inspected in this review. This is a published computational model record; no simulation, calibration or patient-response validation was performed here, and it does not establish daraxonrasib immune or resistance predictions.

{ }

Source YAML

click to show

name: Pancreatic Ductal Adenocarcinoma
creation_date: '2026-03-06T00:00:00Z'
description: >-
  Pancreatic ductal adenocarcinoma (PDAC) is a malignant pancreatic epithelial neoplasm with ductal
  differentiation. Most tumors harbor an activating KRAS mutation together with alterations in tumor-suppressor
  pathways, but KRAS-wild-type tumors include distinct actionable drivers. Acinar reprogramming,
  ductal-origin models and several precursor lesions contribute to current initiation models; ductal
  morphology does not establish a unique human cell of origin. Desmoplastic fibroblast states, myeloid
  and lymphoid suppression, altered antigen presentation, nutrient scavenging and metabolic adaptation
  shape invasion and treatment response. Resectability and metastatic extent determine clinical management.
  Surgery with systemic therapy offers potential long-term control in selected localized disease;
  advanced disease is treated with systemic regimens and, in defined molecular subsets, targeted
  or immune therapies. Daraxonrasib has randomized clinical efficacy in previously treated metastatic
  PDAC. Its resistance mechanisms now have paired clinical ctDNA evidence, whereas immune-remodeling/checkpoint
  combinations remain preclinical.
categories:
- Solid Tumor
- Gastrointestinal Cancer
- Adenocarcinoma
parents:
- pancreatic cancer
has_subtypes:
- name: Classical Subtype
  description: >-
    An expression program enriched for epithelial differentiation. Classical and basal-like states
    can coexist within a tumor; bulk-expression assignments do not imply immutable, mutually exclusive
    diseases. The original virtual-microdissection cohorts associated classical tumors with better
    survival than basal-like tumors.
  evidence:
  - reference: PMID:26343385
    reference_title: Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      we have identified and validated two tumor subtypes, including a 'basal-like'
      subtype that has worse outcome and is molecularly similar to basal tumors in
      bladder and breast cancers.
    explanation: >-
      Moffitt et al. used virtual microdissection of gene expression data to identify
      classical and basal-like subtypes of PDAC, with classical having better prognosis.
- name: Basal-like Subtype
  description: >-
    A basal/squamous expression program associated with adverse outcome in the original profiling
    cohorts. State abundance and plasticity vary within tumors and under treatment. In autochthonous
    mouse PDAC, basal-state ablation or basal-cell GM-CSF loss disrupted an immunosuppressive circuit
    and reduced tumors; this is not yet a validated human state-selective treatment.
  evidence:
  - reference: PMID:26343385
    reference_title: Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      patients with basal-like subtype tumors had an overall worse median survival of
      11 months and 44% 1-year survival compared to 19 months and 70% 1-year survival
      for those with classical subtype tumors
    explanation: >-
      Moffitt et al. demonstrated basal-like subtype has significantly worse survival
      compared to classical subtype in PDAC.
  - reference: PMID:42523238
    reference_title: The basal cell state maintains pancreatic cancers by controlling an immunosuppressive circuit.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Knockout of a single cytokine, GM-CSF, specifically in basal cells recapitulated macrophage repolarization and lymphocyte recruitment observed upon basal state ablation and shrank tumors.
    explanation: >-
      Basal-cell-specific genetic perturbation establishes an immune-organizing GM-CSF role in mouse
      PDAC. Human prognostic association does not establish the same intervention effect.
stages:
- name: Resectable
  description: >-
    Localized disease judged technically resectable by multidisciplinary pancreatic-protocol imaging
    and clinical assessment. Pancreaticoduodenectomy or distal pancreatectomy is selected by location;
    postoperative systemic therapy is standard for suitable patients.
- name: Borderline Resectable
  description: >-
    Localized disease with a high risk of margin-positive resection, commonly related to vascular
    involvement. Induction therapy and reassessment guide consideration of surgery.
  evidence:
  - reference: PMID:41067164
    reference_title: Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with pancreatic cancer.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Patients with borderline resectable pancreatic cancer have a high probability of an R1 resection and should be considered for induction treatment
    explanation: >-
      Consensus recommendation links borderline resectability to margin risk and induction treatment.
- name: Locally Advanced
  description: >-
    Nonmetastatic disease with local involvement precluding upfront resection. Systemic treatment,
    symptom care and reassessment for selected local approaches are appropriate.
- name: Metastatic
  description: >-
    Distant spread, commonly to liver, peritoneum or lung, requires systemic and supportive care.
    The metastasis, RAS-inhibitor resistance and immune-remodeling mechanisms belong to this PDAC
    model rather than a separate disease.
pathophysiology:
- name: Chronic Pancreatic Inflammation
  conforms_to: tumor_promoting_inflammation#Chronic Inflammatory Stimulus
  description: >-
    Inflammation and tissue injury can cooperate with oncogenic KRAS to enable acinar reprogramming
    and precursor formation. In one adult acinar/centroacinar KRAS-G12V mouse model, chronic pancreatitis
    was necessary for tumor induction. This is a model-specific requirement, not a claim that every
    human PDAC requires clinically recognized pancreatitis. Human chronic pancreatitis is a strong
    risk factor with risk estimates dependent on follow-up and case definition.
  biological_scale: TISSUE
  role: trigger
  locations:
  - preferred_term: pancreas
    term:
      id: UBERON:0001264
      label: pancreas
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: pancreatic stellate cell
    term:
      id: CL:0002410
      label: pancreatic stellate cell
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:17349585
    reference_title: Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: These observations suggest that, during adulthood, PDA stems from a combination of genetic (e.g., somatic K-Ras mutations) and nongenetic (e.g., tissue damage) events.
    explanation: >-
      States the two-component model directly: the genetic lesion is modeled by the
      KRAS node and the nongenetic tissue-damage component is what this node is for.
  - reference: PMID:35142721
    reference_title: 'Chronic Pancreatitis Is a Risk Factor for Pancreatic Cancer, and Incidence Increases With Duration of Disease: A Systematic Review and Meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There is an increased risk of PDAC in patients with CP, and incidence rates increase with CP disease duration.
    explanation: >-
      The human counterpart of the mouse result, with risk rising as the inflammation
      persists. PARTIAL because it measures cancer incidence in inflamed pancreata
      rather than anything at this node itself.
  downstream:
  - target: Acinar-to-Ductal Metaplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Injury promotes ductal reprogramming in permissive pancreatic cells.
    evidence:
    - reference: PMID:17349585
      reference_title: Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: These observations suggest that, during adulthood, PDA stems from a combination of genetic (e.g., somatic K-Ras mutations) and nongenetic (e.g., tissue damage) events.
      explanation: >-
        States the two-component model directly: the genetic lesion is modeled by the
        KRAS node and the nongenetic tissue-damage component is what this node is for.
    - reference: PMID:35142721
      reference_title: 'Chronic Pancreatitis Is a Risk Factor for Pancreatic Cancer, and Incidence Increases With Duration of Disease: A Systematic Review and Meta-analysis.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: There is an increased risk of PDAC in patients with CP, and incidence rates increase with CP disease duration.
      explanation: >-
        The human counterpart of the mouse result, with risk rising as the inflammation
        persists. PARTIAL because it measures cancer incidence in inflamed pancreata
        rather than anything at this node itself.
  - target: Early Dissemination and EMT
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Pancreatitis increased circulating pancreatic cells and EMT-associated dissemination in lineage-traced
      mice.
    evidence:
    - reference: PMID:22265420
      reference_title: EMT and dissemination precede pancreatic tumor formation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: EMT and invasiveness were most abundant at inflammatory foci, and induction of pancreatitis increased the number of circulating pancreatic cells.
      explanation: >-
        Experimental pancreatitis perturbs early dissemination within this mouse model.
- name: Acinar-to-Ductal Metaplasia
  description: >-
    Acinar cells can lose differentiated identity and adopt ductal-like programs during injury and
    KRAS-driven transformation. ADM is reversible in regenerative settings and is not synonymous
    with cancer. Persistent oncogenic signaling can channel reprogrammed cells into PanIN. Adult
    ductal cells can also initiate PDAC with cooperating p53 alterations in mice; the relative contribution
    of these origins in humans remains unresolved.
  biological_scale: CELLULAR
  role: mediator
  cell_types:
  - preferred_term: pancreatic acinar cell
    term:
      id: CL:0002064
      label: pancreatic acinar cell
  - preferred_term: pancreatic ductal cell
    term:
      id: CL:0002079
      label: pancreatic ductal cell
  biological_processes:
  - preferred_term: transdifferentiation
    modifier: INCREASED
    term:
      id: GO:0060290
      label: transdifferentiation
  evidence:
  - reference: PMID:35176433
    reference_title: Ductal metaplasia in pancreas.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Acinar to ductal metaplasia (ADM) is the predominant form of ductal metaplasia in pancreas.
    explanation: >-
      Establishes ADM as the dominant metaplastic route in this organ, which is what
      this node models.
  - reference: PMID:17349585
    reference_title: Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: suggesting that PDA originates by differentiation of acinar/centroacinar cells or their precursors into ductal-like cells
    explanation: >-
      Lineage evidence that the ductal-like cells of PDAC descend from the acinar
      compartment, which is the transdifferentiation this node annotates.
  - reference: PMID:26592447
    reference_title: p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: These data demonstrate that pancreatic ductal cells, whereas exhibiting relative resistance to oncogenic Kras alone, can serve as an effective cell of origin for pancreatic ductal adenocarcinoma in the setting of gain-of-function mutations in p53.
    explanation: >-
      Ductal-origin mouse experiments refute exclusive acinar origin.
  downstream:
  - target: Pancreatic Precursor Progression and Invasive Growth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Persistent reprogramming can precede PanIN and invasive progression in an oncogenic context;
      regenerative ADM alone is insufficient.
    evidence:
    - reference: PMID:35176433
      reference_title: Ductal metaplasia in pancreas.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Acinar to ductal metaplasia (ADM) is the predominant form of ductal metaplasia in pancreas.
      explanation: >-
        Establishes ADM as the dominant metaplastic route in this organ, which is what
        this node models.
- name: KRAS Oncogene Activation
  conforms_to: sustaining_proliferative_signaling#Constitutive Mitogenic Pathway Activation
  description: >-
    Activating KRAS variants favor persistent RAS-GTP signaling through RAF-MEK-ERK and additional
    effector networks, supporting proliferation, survival, metabolic rewiring and microenvironmental
    remodeling. G12D, G12V and G12R are common in PDAC, with allele-specific signaling and inhibitor
    responses. Most PDACs are KRAS-mutant; KRAS-wild-type cancers require separate driver characterization.
    KRAS signaling does not itself establish acquisition of a particular tumor-suppressor mutation
    or therapeutic inhibition.
  evidence:
  - reference: PMID:35302596
    reference_title: Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: KRAS mutation (MT) is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC).
    explanation: This directly supports KRAS as the central driver pathway in PDAC.
  - reference: DOI:10.3389/fmed.2024.1369136
    reference_title: 'Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In the case of pancreatic ductal adenocarcinomas (PDAC), 90–92% harbor mutations in the oncogene KRAS, triggering canonical MAPK signaling.
    explanation: >-
      Review-level estimate and signaling background; precise frequencies vary by assay and cohort.
  - reference: DOI:10.1093/carcin/bgae064
    reference_title: 'From precursor to cancer: decoding the intrinsic and extrinsic pathways of pancreatic intraepithelial neoplasia progression'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PanIN development begins with Kirsten rat sarcoma viral oncogene (KRAS) mutations
      driving PanIN initiation. Key additional mutations in cyclin-dependent kinase
      inhibitor 2A (CDKN2A), tumor protein p53 (TP53), and mothers against decapentaplegic
      homolog 4 (SMAD4) disrupt cell cycle control and genomic stability, crucial for
      PanIN progression from low-grade to high-grade dysplasia.
    explanation: >-
      This review confirms KRAS mutations as the initiating event in PanIN development,
      with additional tumor suppressor losses driving progression to invasive carcinoma.
  genetic_context:
    gene:
      preferred_term: KRAS
      term:
        id: hgnc:6407
        label: KRAS
    variant_origin: SOMATIC
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      Somatic activating KRAS codon-12 mutation, the initiating lesion of the
      PanIN-to-PDAC sequence, arising in the acinar/centroacinar compartment. The
      tumour's ductal phenotype is acquired downstream through acinar-to-ductal
      metaplasia and does not indicate a ductal cell of origin.
  cell_types:
  - preferred_term: pancreatic acinar cell
    term:
      id: CL:0002064
      label: pancreatic acinar cell
  biological_processes:
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
  - preferred_term: phosphatidylinositol 3-kinase signaling
    modifier: INCREASED
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  downstream:
  - target: Acinar-to-Ductal Metaplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      KRAS promotes persistent ductal reprogramming in susceptible acinar cells; injury, lineage
      and cooperating alterations modify this effect.
    evidence:
    - reference: PMID:35176433
      reference_title: Ductal metaplasia in pancreas.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Acinar to ductal metaplasia (ADM) is the predominant form of ductal metaplasia in pancreas.
      explanation: >-
        Establishes ADM as the dominant metaplastic route in this organ, which is what
        this node models.
  - target: KRAS-Dependent Anabolic Glucose Metabolism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Oncogenic KRAS regulates this growth-supporting metabolic program in the cited experimental
      context.
    evidence:
    - reference: PMID:22541435
      reference_title: Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Transcriptome and metabolomic analyses indicate that Kras(G12D) serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP).
      explanation: >-
        Genetic KRAS withdrawal and metabolic profiling establish the growth-supporting program.
  - target: KRAS-Regulated Glutamine Redox Metabolism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Oncogenic KRAS regulates this growth-supporting metabolic program in the cited experimental
      context.
    evidence:
    - reference: PMID:23535601
      reference_title: Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Furthermore, we establish that the reprogramming of glutamine metabolism is mediated by oncogenic KRAS
      explanation: >-
        Genetic experiments connect KRAS to the noncanonical glutamine pathway.
  - target: Macropinocytic Protein Scavenging
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Oncogenic KRAS regulates this growth-supporting metabolic program in the cited experimental
      context.
    evidence:
    - reference: PMID:23665962
      reference_title: Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism.
      explanation: >-
        Protein uptake supplies usable metabolites in Ras-transformed cellular models.
  - target: KRAS-GM-CSF Myeloid Immunosuppression
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Oncogenic KRAS induces GM-CSF-dependent myeloid suppression.
    evidence:
    - reference: PMID:22698407
      reference_title: Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Kras(G12D)-dependent production of GM-CSF in vivo is required for the recruitment of Gr1(+)CD11b(+) myeloid cells.
      explanation: >-
        Primary mechanistic study links oncogenic KRAS to GM-CSF-dependent immune suppression.
    intermediate_mechanisms:
    - Tumor-cell GM-CSF production
    - Expansion of suppressive myeloid cells
  - target: USP20 Cholesterol-Metabolism CD8 Exhaustion Checkpoint
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      KRAS-G12D induces EGR1-USP20, coordinating cholesterol metabolism and compensatory survival.
    evidence:
    - reference: PMID:42392864
      reference_title: USP20 promotes CD8(+) T cell exhaustion and impairs KRAS(G12D) inhibitor efficacy by orchestrating cholesterol metabolism and autophagy in pancreatic cancer.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Mechanistically, KRASG12D transcriptionally upregulated USP20 via EGR1, which simultaneously deubiquitinated and stabilised 3-hydroxy-3-methylglutaryl-CoA reductase and ULK1, thereby orchestrating cholesterol metabolism and autophagy-associated survival.
      explanation: >-
        Mechanistic preclinical experiments relate USP20 to cholesterol and autophagy; the cohort
        provides human-tissue context.
    intermediate_mechanisms:
    - EGR1-dependent USP20 expression
    - HMG-CoA reductase stabilization
- name: Tumor Suppressor Inactivation
  conforms_to: evading_growth_suppressors#Tumor Suppressor Inactivation
  description: >-
    Alterations of CDKN2A, TP53 and SMAD4 cooperate with oncogenic signaling. Loss of p16 removes
    restraint on CDK4/6-RB cell-cycle progression; p53 alterations weaken stress checkpoints and
    can confer context-dependent gain of function; SMAD4 loss changes TGF-beta responses. Reported
    alteration frequencies differ with cohort, assay, copy-number detection and inclusion of epigenetic
    silencing. These are cooperating events rather than consequences inferred from co-occurrence
    with KRAS.
  evidence:
  - reference: PMID:18772397
    reference_title: Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This list includes the classic tumor suppressor genes CDKN2A (p16), SMAD4,
      and TP53, as well as genes that had not previously been implicated in pancreatic
      cancer development.
    explanation: >-
      The landmark Jones et al. genomic analysis identified CDKN2A, SMAD4, and TP53 as
      core tumor suppressor genes in pancreatic cancer through global sequencing of 24
      advanced pancreatic adenocarcinomas.
  biological_processes:
  - preferred_term: regulation of cell cycle
    modifier: ABNORMAL
    term:
      id: GO:0051726
      label: regulation of cell cycle
  - preferred_term: apoptotic process
    modifier: DECREASED
    term:
      id: GO:0006915
      label: apoptotic process
  - preferred_term: DNA damage response
    modifier: ABNORMAL
    term:
      id: GO:0006974
      label: DNA damage response
  downstream:
  - target: Pancreatic Precursor Progression and Invasive Growth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Checkpoint and differentiation defects cooperate with KRAS to permit invasive progression.
    evidence:
    - reference: PMID:26592447
      reference_title: p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: In contrast to the lack of response to oncogenic Kras alone, simultaneous activation of Kras and mutant p53 in adult ductal epithelium generated invasive PDAC in 75% of mice as early as 2.5 months after tamoxifen administration.
      explanation: >-
        Cooperating oncogenic KRAS and mutant p53 enable invasive cancer in ductal-origin mice.
- name: Pancreatic Precursor Progression and Invasive Growth
  description: >-
    KRAS-mutant PanIN can progress with cooperating genetic and microenvironmental changes to invasive,
    gland-forming PDAC. IPMN and mucinous cystic neoplasms provide additional precursor routes. Not
    every precursor progresses, and a uniform obligatory mutation order or exclusive acinar origin
    is not established.
  evidence:
  - reference: PMID:17349585
    reference_title: Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: However, if these mice are challenged with a mild form of chronic pancreatitis, they develop the full spectrum of PanINs and invasive PDA.
    explanation: >-
      Genetic and inflammatory cooperation supports progression in the defined mouse model.
  - reference: PMID:26592447
    reference_title: p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In contrast to the lack of response to oncogenic Kras alone, simultaneous activation of Kras and mutant p53 in adult ductal epithelium generated invasive PDAC in 75% of mice as early as 2.5 months after tamoxifen administration.
    explanation: >-
      Cooperating oncogenic KRAS and mutant p53 enable invasive cancer in ductal-origin mice.
  downstream:
  - target: Desmoplastic Stroma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Tumor-secreted ligands promote fibroblast-state changes and matrix-producing stroma.
    evidence:
    - reference: PMID:30366930
      reference_title: IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Here, we use organoid and mouse models to identify TGFβ and IL1 as tumor-secreted ligands that promote CAF heterogeneity.
      explanation: >-
        Tumor-secreted signals establish heterogeneous stromal responses.
  - target: Metastatic Dissemination and Colonization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Invasive growth enables dissemination, but the timing and route vary across tumors.
    evidence:
    - reference: PMID:25985394
      reference_title: Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden.
      explanation: >-
        The primary study experimentally connects extracellular vesicles to a permissive liver niche.
  - target: IL1-LIF-JAK-STAT Inflammatory Fibroblast Programming
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Tumor-derived IL1α secretion
    - Fibroblast IL1R1 signaling and LIF induction
    description: >-
      The neoplastic epithelial compartment can induce inflammatory fibroblast differentiation
      through secreted IL1α in PDAC organoid-stellate-cell systems. This branch represents signals
      from established tumors, not a claim that invasion itself or extracellular matrix deposition
      directly induces every iCAF state; other ligands contribute in vivo.
    evidence:
    - reference: PMID:30366930
      reference_title: IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Levels of the iCAF markers were significantly reduced when PSCs were cultured with IL-1α
        knockout organoids compared to Rosa26-targeted control organoids, while levels of the myCAF
        marker αSMA were significantly increased (Figure 2D).
      explanation: >-
        Genetic deletion in tumor organoids directly tests the epithelial-to-fibroblast signal in
        vitro; the study separately reports incomplete suppression of the inflammatory phenotype after
        tumor IL1α deletion in vivo.
  - target: Tumor-Restraining Fibroblast Programs
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Tumor-derived SHH secretion
    - Stromal Hedgehog pathway activation and fibroblast expansion
    description: >-
      Neoplastic cells can establish a Hedgehog-responsive fibroblast-rich stroma with
      tumor-restraining activity in a genetically engineered PDAC mouse model. This incoming branch
      concerns the SHH-dependent component of the heterogeneous stromal node, not all fibroblast
      states or a universal protective role for fibrosis.
    evidence:
    - reference: PMID:24856585
      reference_title: "Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Sonic hedgehog (Shh), a soluble ligand overexpressed by neoplastic cells in pancreatic ductal
        adenocarcinoma (PDAC), drives formation of a fibroblast-rich desmoplastic stroma.
      explanation: >-
        The source identifies the tumor-derived ligand and stromal response; the genetic perturbation
        below tests its restraining function in mice.
    - reference: PMID:24856585
      reference_title: "Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        As predicted, Shh-deficient tumors had reduced stromal content. Surprisingly, such tumors were
        more aggressive and exhibited undifferentiated histology, increased vascularity, and
        heightened proliferation--features that were fully recapitulated in control mice treated with
        a Smoothened inhibitor.
      explanation: >-
        Loss of tumor SHH or pharmacologic Hedgehog inhibition reduced stroma and increased aggressive
        growth in this model. The edge does not equate SHH-driven stroma with every alphaSMA-positive,
        inflammatory or interferon-responsive fibroblast population.
  - target: Pancreatic Exocrine Functional Loss
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Main pancreatic duct obstruction
    - Gland fibrosis and loss of exocrine tissue
    description: >-
      An established pancreatic tumor can impair exocrine secretion through duct obstruction and
      loss of functional tissue. Risk depends on tumor location and extent; this is not an
      obligatory consequence of a noninvasive precursor, and postoperative insufficiency has an
      additional surgical cause.
    evidence:
    - reference: PMID:32631175
      reference_title: "Pancreatic exocrine insufficiency and pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer: A systematic review and meta-analysis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        PEI seems to be one of the determinant factors of malnutrition in APC due to obstruction of
        the main pancreatic duct, fibrosis of the gland and loss of pancreatic exocrine tissue.
      explanation: >-
        The systematic review describes the anatomic mechanisms of exocrine insufficiency in advanced
        pancreatic cancer in its background; the pooled prevalence is not evidence that every
        precursor causes insufficiency.
  - target: Obstructive Jaundice
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Biliary obstruction from a pancreatic head tumor
    description: >-
      An obstructive pancreatic head cancer can impair bile drainage and cause jaundice. This
      location-dependent consequence of established tumor growth is not attributed to all PDAC or to
      noninvasive precursors.
    evidence:
    - reference: PMID:41067164
      reference_title: "Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with pancreatic cancer."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        in case of jaundice due to an obstructive head pancreatic cancer, imaging should be carried
        out before biliary drainage or stenting
      explanation: >-
        The guideline explicitly identifies jaundice due to an obstructive pancreatic head cancer and
        recommends imaging before drainage. This supports the anatomic causal route without estimating
        its frequency.
- name: Desmoplastic Stroma
  description: >-
    Tumor-derived signals and local tissue interactions recruit and alter fibroblast states that
    deposit collagen, hyaluronan and other extracellular matrix. Dense matrix can impair perfusion,
    but stromal programs are heterogeneous: some support inflammation or immune exclusion and others
    restrain tumor growth. Fibroblast depletion and matrix digestion are not interchangeable, and
    neither is a generally validated treatment for PDAC.
  evidence:
  - reference: PMID:30366930
    reference_title: IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Here, we use organoid and mouse models to identify TGFβ and IL1 as tumor-secreted ligands that promote CAF heterogeneity.
    explanation: >-
      Tumor-secreted signals establish heterogeneous stromal responses.
  cell_types:
  - preferred_term: pancreatic stellate cell
    term:
      id: CL:0002410
      label: pancreatic stellate cell
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: INCREASED
    term:
      id: GO:0030198
      label: extracellular matrix organization
  - preferred_term: collagen biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0032964
      label: collagen biosynthetic process
  downstream:
  - target: CAF-Mediated T Cell Exclusion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The FAP-positive CXCL12-producing subset supports spatial immune exclusion.
    evidence:
    - reference: PMID:24277834
      reference_title: Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Administering AMD3100, a CXCL12 receptor chemokine (C-X-C motif) receptor 4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with α-PD-L1 to greatly diminish cancer cells
      explanation: >-
        Perturbation supports CXCL12-CXCR4-mediated immune exclusion in a mouse PDAC model.
    intermediate_mechanisms:
    - FAP-positive fibroblast CXCL12 secretion
    - CXCR4-dependent T-cell exclusion
  - target: Matrix-Associated Hypoperfusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Matrix accumulation can impair vascular perfusion.
    evidence:
    - reference: PMID:22439937
      reference_title: Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: We show here that this desmoplastic reaction generates inordinately high interstitial fluid pressures (IFPs), exceeding those previously measured or theorized for solid tumors, and induces vascular collapse, while presenting substantial barriers to perfusion, diffusion, and convection of small molecule therapeutics.
      explanation: >-
        Primary mouse study supports a physical stromal barrier.
- name: CAF-Mediated T Cell Exclusion
  description: >-
    FAP-positive fibroblasts can supply CXCL12 that localizes around malignant cells and limits T-cell
    access. In KPC mouse tumors, CXCR4 inhibition rapidly increased T-cell accumulation and synergized
    with PD-L1 blockade. This identifies a specific stromal immune-exclusion circuit, not uniform
    behavior of all fibroblasts.
  cell_types:
  - preferred_term: pancreatic stellate cell
    term:
      id: CL:0002410
      label: pancreatic stellate cell
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: chemokine-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0070098
      label: chemokine-mediated signaling pathway
  - preferred_term: Negative Regulation of T Cell Mediated Immunity
    modifier: INCREASED
    term:
      id: GO:0002710
      label: negative regulation of T cell mediated immunity
  evidence:
  - reference: PMID:24277834
    reference_title: Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Administering AMD3100, a CXCL12 receptor chemokine (C-X-C motif) receptor 4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with α-PD-L1 to greatly diminish cancer cells
    explanation: >-
      Perturbation supports CXCL12-CXCR4-mediated immune exclusion in a mouse PDAC model.
  genes:
  - preferred_term: CXCL12
    term:
      id: hgnc:10672
      label: CXCL12
  - preferred_term: CXCR4
    term:
      id: hgnc:2561
      label: CXCR4
  - preferred_term: FAP
    term:
      id: hgnc:3590
      label: FAP
  downstream:
  - target: Immune Evasion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The specified mechanism limits effective antitumor T-cell control.
    evidence:
    - reference: PMID:24277834
      reference_title: Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Administering AMD3100, a CXCL12 receptor chemokine (C-X-C motif) receptor 4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with α-PD-L1 to greatly diminish cancer cells
      explanation: >-
        Perturbation supports CXCL12-CXCR4-mediated immune exclusion in a mouse PDAC model.
- name: IL1-LIF-JAK-STAT Inflammatory Fibroblast Programming
  description: >-
    Tumor-derived IL1 induces fibroblast LIF and JAK-STAT signaling, promoting an inflammatory CAF
    state. TGF-beta antagonizes this program by reducing IL1R1 and favoring myofibroblasts. Spatial
    exposure and plasticity generate distinct CAF niches, so fibroblast number alone is an inadequate
    mechanistic readout.
  evidence:
  - reference: PMID:30366930
    reference_title: IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We show that IL1 induces LIF expression and downstream JAK/STAT activation to generate inflammatory CAFs and demonstrate that TGFβ antagonizes this process by downregulating IL1R1 expression and promoting differentiation into myofibroblasts.
    explanation: >-
      Directly distinguishes competing CAF programs.
- name: Tumor-Restraining Fibroblast Programs
  description: >-
    Some fibroblast and stromal programs constrain PDAC. Genetic SHH loss and depletion of alpha-SMA-positive
    myofibroblasts in distinct mouse models accelerated aggressive disease; newer interferon-response
    CAF work also identifies a restraining state. These findings qualify global stroma-removal strategies
    without proving that every myofibroblast state is protective.
  evidence:
  - reference: PMID:24856585
    reference_title: Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth.
    explanation: >-
      The primary genetic stromal-perturbation study establishes an important counterexample to uniformly
      tumor-promoting stroma.
  - reference: PMID:24856586
    reference_title: Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Suppressed immune surveillance with increased CD4(+)Foxp3(+) Tregs was observed in myofibroblast-depleted mouse tumors.
    explanation: >-
      Myofibroblast depletion worsened mouse disease; intervention and source scope are explicit.
- name: Matrix-Associated Hypoperfusion
  description: >-
    Hyaluronan-rich stroma can elevate interstitial fluid pressure, collapse vessels and restrict
    delivery of nutrients and drugs in PDAC mouse models. Matrix degradation improved perfusion experimentally,
    but the phase III PEGPH20 trial did not improve survival, limiting direct therapeutic extrapolation.
  evidence:
  - reference: PMID:22439937
    reference_title: Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We show here that this desmoplastic reaction generates inordinately high interstitial fluid pressures (IFPs), exceeding those previously measured or theorized for solid tumors, and induces vascular collapse, while presenting substantial barriers to perfusion, diffusion, and convection of small molecule therapeutics.
    explanation: >-
      Primary mouse study supports a physical stromal barrier.
- name: KRAS-Dependent Anabolic Glucose Metabolism
  description: >-
    KRAS supports glucose uptake and redirects intermediates toward anabolic pathways that sustain
    pancreatic tumor growth. This is a regulated metabolic program rather than a universal switch
    eliminating oxidative phosphorylation.
  evidence:
  - reference: PMID:22541435
    reference_title: Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Transcriptome and metabolomic analyses indicate that Kras(G12D) serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP).
    explanation: >-
      Genetic KRAS withdrawal and metabolic profiling establish the growth-supporting program.
  biological_processes:
  - preferred_term: glycolytic process
    modifier: INCREASED
    term:
      id: GO:0006096
      label: glycolytic process
  downstream:
  - target: Pancreatic Precursor Progression and Invasive Growth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Nutrient use and redox support permit continued malignant growth.
    evidence:
    - reference: PMID:22541435
      reference_title: Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Transcriptome and metabolomic analyses indicate that Kras(G12D) serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP).
      explanation: >-
        Genetic KRAS withdrawal and metabolic profiling establish the growth-supporting program.
- name: KRAS-Regulated Glutamine Redox Metabolism
  description: >-
    In studied PDAC cells, glutamine-derived aspartate is routed through cytosolic GOT1, malate and
    pyruvate to support NADPH-dependent redox balance. Dependency varies with growth context and
    compensatory metabolism; this does not establish clinical efficacy of glutaminase inhibition.
  evidence:
  - reference: PMID:23535601
    reference_title: Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Furthermore, we establish that the reprogramming of glutamine metabolism is mediated by oncogenic KRAS
    explanation: >-
      Genetic experiments connect KRAS to the noncanonical glutamine pathway.
  genes:
  - preferred_term: GOT1
    term:
      id: hgnc:4432
      label: GOT1
  downstream:
  - target: Pancreatic Precursor Progression and Invasive Growth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Nutrient use and redox support permit continued malignant growth.
    evidence:
    - reference: PMID:23535601
      reference_title: Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Furthermore, we establish that the reprogramming of glutamine metabolism is mediated by oncogenic KRAS
      explanation: >-
        Genetic experiments connect KRAS to the noncanonical glutamine pathway.
- name: Macropinocytic Protein Scavenging
  description: >-
    RAS-driven macropinocytosis internalizes extracellular protein for lysosomal proteolysis and
    amino-acid supply. It supports growth in nutrient-poor settings and is observed in primary human
    PDAC specimens, complementing transport of free nutrients.
  evidence:
  - reference: PMID:23665962
    reference_title: Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism.
    explanation: >-
      Protein uptake supplies usable metabolites in Ras-transformed cellular models.
  - reference: PMID:25644265
    reference_title: Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Consistent with this hypothesis, active macropinocytosis is observed in primary human PDAC specimens.
    explanation: >-
      Human tissue supports relevance, without establishing universal flux or dependency.
  biological_processes:
  - preferred_term: macropinocytosis
    modifier: INCREASED
    term:
      id: GO:0044351
      label: macropinocytosis
  downstream:
  - target: Pancreatic Precursor Progression and Invasive Growth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Nutrient use and redox support permit continued malignant growth.
    evidence:
    - reference: PMID:23665962
      reference_title: Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism.
      explanation: >-
        Protein uptake supplies usable metabolites in Ras-transformed cellular models.
- name: Autophagy-Lysosome Growth Support
  description: >-
    Basal autophagy can maintain oxidative metabolism and restrain damaging reactive oxygen species
    in established pancreatic cancer models. Recycling also provides substrates under treatment stress.
    The effects of autophagy loss differ by tumor stage and genetic context; preclinical dependency
    is not a validated universal treatment response.
  evidence:
  - reference: PMID:21406549
    reference_title: Pancreatic cancers require autophagy for tumor growth.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species, elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation.
    explanation: >-
      Direct perturbation demonstrates metabolic support in the tested PDAC cells.
  biological_processes:
  - preferred_term: autophagy
    modifier: INCREASED
    term:
      id: GO:0006914
      label: autophagy
  downstream:
  - target: Pancreatic Precursor Progression and Invasive Growth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Autophagic recycling and redox control support established tumor growth.
    evidence:
    - reference: PMID:21406549
      reference_title: Pancreatic cancers require autophagy for tumor growth.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species, elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation.
      explanation: >-
        Direct perturbation demonstrates metabolic support in the tested PDAC cells.
- name: Immune Evasion
  description: >-
    Myeloid suppression, dysfunctional lymphocytes, stromal exclusion and impaired antigen presentation
    limit immune control in most PDAC. These mechanisms vary between tumors and metastatic sites.
    Rare mismatch-repair-deficient/MSI-high cancers can respond to checkpoint blockade; PDAC is not
    uniformly refractory to every immune or targeted therapy.
  evidence:
  - reference: DOI:10.1186/s12943-023-01813-y
    reference_title: Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC),
      contributing to early metastasis and poor patient survival.
    explanation: >-
      This review establishes immunosuppression as a hallmark of PDAC that contributes
      to metastasis and poor survival, supporting the immune evasion mechanism.
  - reference: DOI:10.1186/s12943-023-01813-y
    reference_title: Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Following chemokine and exosomal guidance, these cells metastasize to the
      organ-specific pre-metastatic niches (PMNs) constituted by local resident cells,
      stromal fibroblasts, and suppressive immune cells, such as the metastasis-associated
      macrophages, neutrophils, and myeloid-derived suppressor cells.
    explanation: >-
      This describes the immune cell populations in PDAC metastatic niches including
      macrophages, neutrophils, and MDSCs that constitute the immunosuppressive
      microenvironment.
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  - preferred_term: tumor-associated macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: immune response
    modifier: DECREASED
    term:
      id: GO:0006955
      label: immune response
- name: KRAS-GM-CSF Myeloid Immunosuppression
  description: >-
    Oncogenic KRAS induces tumor-cell GM-CSF, expanding suppressive myeloid cells that constrain
    cytotoxic T-cell immunity in pancreatic neoplasia models. This supplies a disease-driving counterpart
    to the myeloid remodeling seen after KRAS inhibition.
  evidence:
  - reference: PMID:22698407
    reference_title: Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Kras(G12D)-dependent production of GM-CSF in vivo is required for the recruitment of Gr1(+)CD11b(+) myeloid cells.
    explanation: >-
      Primary mechanistic study links oncogenic KRAS to GM-CSF-dependent immune suppression.
  genes:
  - preferred_term: CSF2
    term:
      id: hgnc:2434
      label: CSF2
  downstream:
  - target: Immune Evasion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The specified mechanism limits effective antitumor T-cell control.
    evidence:
    - reference: PMID:22698407
      reference_title: Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Kras(G12D)-dependent production of GM-CSF in vivo is required for the recruitment of Gr1(+)CD11b(+) myeloid cells.
      explanation: >-
        Primary mechanistic study links oncogenic KRAS to GM-CSF-dependent immune suppression.
- name: NBR1-Mediated MHC-I Autophagic Degradation
  description: >-
    Selective autophagy directs MHC-I to lysosomes through NBR1, reducing surface antigen presentation
    and immune recognition in PDAC models. Autophagy inhibition can restore MHC-I and improve T-cell
    control. This can coexist with RAS-dependent and FAK-dependent regulation; pathway dominance
    or mutual independence has not been established.
  evidence:
  - reference: PMID:32376951
    reference_title: Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1.
    explanation: >-
      Primary study establishes selective antigen-presentation loss through autophagy.
  genes:
  - preferred_term: NBR1
    term:
      id: hgnc:6746
      label: NBR1
  downstream:
  - target: Immune Evasion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The specified mechanism limits effective antitumor T-cell control.
    evidence:
    - reference: PMID:32376951
      reference_title: Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1.
      explanation: >-
        Primary study establishes selective antigen-presentation loss through autophagy.
- name: FAK-Mediated Antigen-Presentation Suppression
  mechanism_confidence: PROVISIONAL
  description: >-
    Tumor-cell FAK signaling limits immunoproteasome expression and antigen presentation in PDAC
    models. FAK depletion increases antigen diversity and MHC-I presentation; combined STAT3 loss
    further promotes immune control. This is a complementary regulator, not evidence that RAS cannot
    influence MHC-I. The reported antigen-presentation effect is kinase-independent, requires nuclear
    FAK, and is lost in an extreme squamous phenotype; FAK kinase inhibition is therefore not equivalent
    to eliminating this function.
  evidence:
  - reference: PMID:36977556
    reference_title: FAK suppresses antigen processing and presentation to promote immune evasion in pancreatic cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Loss of PDAC cell-intrinsic FAK signalling promotes expression of the immunoproteasome and Major Histocompatibility Complex class-I (MHC-I), resulting in increased antigen diversity and antigen presentation by FAK-/- PDAC cells.
    explanation: >-
      The primary study evaluates FAK-dependent immune regulation in pancreatic cancer models.
  genes:
  - preferred_term: PTK2
    term:
      id: hgnc:9611
      label: PTK2
  downstream:
  - target: Immune Evasion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The specified mechanism limits effective antitumor T-cell control.
    evidence:
    - reference: PMID:36977556
      reference_title: FAK suppresses antigen processing and presentation to promote immune evasion in pancreatic cancer.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Loss of PDAC cell-intrinsic FAK signalling promotes expression of the immunoproteasome and Major Histocompatibility Complex class-I (MHC-I), resulting in increased antigen diversity and antigen presentation by FAK-/- PDAC cells.
      explanation: >-
        The primary study evaluates FAK-dependent immune regulation in pancreatic cancer models.
- name: Exosome-MIF Liver Premetastatic Niche
  biological_scale: CELLULAR
  description: >-
    PDAC-derived exosomes carrying MIF can be taken up by Kupffer cells, inducing TGF-beta, hepatic
    stellate-cell fibronectin deposition and recruitment of bone-marrow-derived macrophages. This
    establishes a liver premetastatic niche mechanism; the cited study does not by itself establish
    direct exosomal suppression of dendritic cells or T cells.
  evidence:
  - reference: PMID:25985394
    reference_title: Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor
      β secretion and upregulation of fibronectin production by hepatic stellate cells.
      This fibrotic microenvironment enhanced recruitment of bone marrow-derived
      macrophages.
    explanation: >-
      The primary study supports exosomal MIF-driven liver niche formation and metastasis, not direct
      proof of lymphocyte suppression.
  - reference: PMID:25985394
    reference_title: Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found that macrophage migration inhibitory factor (MIF) was highly expressed in
      PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche
      formation and metastasis.
    explanation: >-
      The primary study supports exosomal MIF-driven liver niche formation and metastasis, not direct
      proof of lymphocyte suppression.
  cell_types:
  - preferred_term: pancreatic ductal cell
    term:
      id: CL:0002079
      label: pancreatic ductal cell
  - preferred_term: Kupffer cell
    term:
      id: CL:0000091
      label: Kupffer cell
  - preferred_term: recruited bone marrow-derived macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: extracellular exosome biogenesis
    modifier: INCREASED
    term:
      id: GO:0097734
      label: extracellular exosome biogenesis
  - preferred_term: transforming growth factor beta production
    modifier: INCREASED
    term:
      id: GO:0071604
      label: transforming growth factor beta production
  downstream:
  - target: Metastatic Dissemination and Colonization
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      MIF-dependent Kupffer-cell and stellate-cell remodeling supports liver colonization.
    evidence:
    - reference: PMID:25985394
      reference_title: Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor
        β secretion and upregulation of fibronectin production by hepatic stellate cells.
        This fibrotic microenvironment enhanced recruitment of bone marrow-derived
        macrophages.
      explanation: >-
        The primary study supports exosomal MIF-driven liver niche formation and metastasis, not
        direct proof of lymphocyte suppression.
    - reference: PMID:25985394
      reference_title: Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We found that macrophage migration inhibitory factor (MIF) was highly expressed in
        PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche
        formation and metastasis.
      explanation: >-
        The primary study supports exosomal MIF-driven liver niche formation and metastasis, not
        direct proof of lymphocyte suppression.
    intermediate_mechanisms:
    - Kupffer-cell TGF-beta release
    - Hepatic stellate-cell fibronectin deposition
    - Macrophage recruitment
- name: Metastatic Dissemination and Colonization
  description: >-
    Invasive tumor cells disseminate and establish distant lesions, frequently in the liver and also
    lung or peritoneum. Colonization depends on both tumor-cell programs and organ-specific niches;
    metastatic-site immune composition differs from the primary tumor. A single EMT program is not
    obligatory for every metastatic event.
  evidence:
  - reference: PMID:25985394
    reference_title: Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden.
    explanation: >-
      The primary study experimentally connects extracellular vesicles to a permissive liver niche.
  downstream:
  - target: Hepatic Metastases
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Hepatic colonization is a common site-specific manifestation among patients presenting with
      metastatic PDAC.
    evidence:
    - reference: PMID:36776324
      reference_title: A population-based study of synchronous distant metastases and prognosis in patients with PDAC at initial diagnosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        There was a highest incidence of liver metastases from pancreatic cancer
        (2387,74.36%), followed by lung (625,19.47%), bone (190,5.92%), and brain
        (8,0.25%).
      explanation: >-
        This population-based study of metastatic PDAC directly identifies liver
        metastases as the most common distant metastatic site at diagnosis.
- name: Early Dissemination and EMT
  conforms_to: invasion_and_metastasis#Epithelial-Mesenchymal Transition Activation
  description: >-
    Epithelial-mesenchymal plasticity can accompany dissemination and drug resistance, but individual
    EMT transcription factors have nonredundant roles. Snail or Twist deletion did not abolish metastasis
    in a KPC study. Early dissemination observed in mouse precursor models is not proof that all
    human PDAC metastasizes before invasion.
  evidence:
  - reference: PMID:22265420
    reference_title: EMT and dissemination precede pancreatic tumor formation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Tagged cells invaded and entered the bloodstream unexpectedly early, before frank malignancy could be detected by rigorous histologic analysis; this behavior was widely associated with epithelial-to-mesenchymal transition (EMT).
    explanation: >-
      Lineage tracking establishes early dissemination in a mouse pancreatic-cancer model, not universal
      timing of human metastasis.
  - reference: PMID:26560028
    reference_title: Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: EMT suppression in the primary tumour does not alter the emergence of invasive PDAC, systemic dissemination or metastasis.
    explanation: >-
      Snail/Twist deletion challenges obligatory EMT in this mouse model; it does not show that all
      EMT programs are irrelevant.
  biological_processes:
  - preferred_term: epithelial to mesenchymal transition
    modifier: INCREASED
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
  - preferred_term: cell migration
    modifier: INCREASED
    term:
      id: GO:0016477
      label: cell migration
- name: Perineural Invasion
  description: >-
    Pancreatic cancer cells interact with nerves and migrate along neural structures. HGF-MET signaling
    can activate mTOR-NGF, promoting nerve recruitment and invasion in experimental models. PNI is
    associated with adverse clinical outcomes and can contribute to pain; it is not established as
    the universal route to distant metastasis. Human NGF/TrkA levels correlate with PNI and pain
    in one tissue cohort, but a prospective resectable cohort found pain did not predict PNI; clinical
    pain and neural invasion are not interchangeable readouts.
  evidence:
  - reference: PMID:35449152
    reference_title: HGF/c-Met pathway facilitates the perineural invasion of pancreatic cancer by activating the mTOR/NGF axis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Activating the HGF/c-Met signaling pathway potentiated the expression of nerve growth factor (NGF) to recruit nerves and promote the PNI.
    explanation: >-
      Direct perturbation supports tumor-nerve crosstalk.
  - reference: PMID:35449152
    reference_title: HGF/c-Met pathway facilitates the perineural invasion of pancreatic cancer by activating the mTOR/NGF axis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: we found that knocking down c-Met expression inhibited cancer cell migration along the nerve, reduced the damage of the sciatic nerve caused by cancer cells and protected the function of the sciatic nerve in vivo.
    explanation: >-
      Mouse nerve-invasion experiments support local injury, not a clinical pain-frequency estimate.
  - reference: PMID:10561305
    reference_title: Nerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Enhanced expression of the NGF/TrkA system may influence perineural invasion and may contribute to the pain syndrome in human pancreatic cancer.
    explanation: >-
      Human tissue association supports biological relevance while preserving the authors causal
      uncertainty.
  - reference: PMID:28785934
    reference_title: Prospective Evaluation of Associations between Cancer-Related Pain and Perineural Invasion in Patients with Resectable Pancreatic Adenocarcinoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Preoperative pain does not predict the presence of perineural invasion or other pathologic prognostic factors in patients with resectable pancreatic adenocarcinoma.
    explanation: >-
      Prospective 52-patient resectable cohort qualifies pain as a neural-invasion surrogate.
  biological_processes:
  - preferred_term: positive regulation of cell migration
    modifier: INCREASED
    term:
      id: GO:0030335
      label: positive regulation of cell migration
- name: Immunosuppressive TME Reversibility under RAS(ON) Inhibition
  biological_scale: TISSUE
  description: >-
    In immunocompetent PDAC models, RAS(ON) multiselective inhibition can reduce suppressive myeloid
    subsets, increase tumor MHC-I and lymphocyte infiltration, and enable immune-dependent tumor
    control. RMC-7977 and daraxonrasib provide direct PDAC evidence. Responses and optimal checkpoint
    partners are model-dependent; increased Tregs and adaptive myeloid rebound can limit benefit.
    Patient survival from daraxonrasib monotherapy does not establish an immune-mediated clinical
    benefit.
  evidence:
  - reference: PMID:40057911
    reference_title: T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In this study, we report that RAS(ON) multi-selective inhibition led to rapid and profound PDAC regressions in immunocompetent mice, decreasing myeloid cells and increasing T cells and macrophages in the tumor microenvironment.
    explanation: >-
      Direct PDAC evidence was omitted from the immune report despite being cited in the resistance
      report.
  - reference: PMID:40057911
    reference_title: T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The depth and duration of tumor regression depended on T cells and conventional dendritic cells.
    explanation: >-
      Depletion/genetic experiments establish immune contribution in mouse PDAC.
- name: Cyclophilin A Loss and Reduced Tri-Complex Engagement
  biological_scale: MOLECULAR
  description: >-
    A preprint reports reduced cyclophilin-A protein with retained KRAS-G12D-GTP signaling in daraxonrasib-resistant
    PDAC cells. As cyclophilin A is required for tri-complex formation, reduced availability is a
    plausible drug-engagement escape mechanism. This observation does not establish that peptidyl-prolyl
    isomerase catalytic activity was measured or is causally required. The single clinical case in
    this paper instead concerns KRAS-G12R EGFR/wild-type-RAS activation.
  genes:
  - preferred_term: PPIA
    term:
      id: hgnc:9253
      label: PPIA
  evidence:
  - reference: PMID:42465401
    reference_title: 'Overcoming Daraxonrasib Resistance: Allele-Specific Mechanisms Guide Salvage Therapy in Pancreatic Cancer.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In contrast, KRAS G12D resistance arose through retained KRAS G12D -GTP signaling, with a decrease of cyclophilin A (CypA) protein, the binding partner required for daraxonrasib activity.
    explanation: >-
      Preprint cellular evidence for cyclophilin-A protein loss in the G12D context.
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Acquired RAS(ON) Inhibitor Resistance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Under the specified RAS-inhibitor exposure, this route can sustain tumor growth or reduce target
      inhibition. Source and regimen restrictions apply.
    evidence:
    - reference: PMID:42465401
      reference_title: 'Overcoming Daraxonrasib Resistance: Allele-Specific Mechanisms Guide Salvage Therapy in Pancreatic Cancer.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In contrast, KRAS G12D resistance arose through retained KRAS G12D -GTP signaling, with a decrease of cyclophilin A (CypA) protein, the binding partner required for daraxonrasib activity.
      explanation: >-
        Preprint cellular evidence for cyclophilin-A protein loss in the G12D context.
    hypothesis_groups:
    - ras_on_inhibitor_acquired_resistance
- name: RAS-Independent Cell-Cycle Uncoupling
  biological_scale: CELLULAR
  description: >-
    A preprint describes acquired RMC-6236 resistance in mixed PDAC and NSCLC models with sustained
    cell-cycle progression despite RAS suppression. CDK4/6 or CDK2 cotargeting restored control through
    distinct arrest programs; CDK2 inhibition produced more durable cytostasis in the tested settings.
    This is not a clinically validated combination or proof that simultaneous inhibition of all three
    kinases is required. CDK8-mediated microenvironmental resistance is a separate mechanism.
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:41959066
    reference_title: Targeting Distinct Cell Cycle Nodes Overcomes KRAS/RAS Inhibitor Resistance.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: While these pathways can be broadly inhibited using the pan-RAS-ON inhibitor RMC-6236, cells remained capable of developing acquired resistance where cell proliferation is uncoupled from RAS signaling.
    explanation: >-
      Preprint directly models RMC-6236 resistance in cellular systems.
  - reference: PMID:41959066
    reference_title: Targeting Distinct Cell Cycle Nodes Overcomes KRAS/RAS Inhibitor Resistance.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Finally, concurrent inhibition of KRAS with either CDK4/6 or CDK2 yields durable tumor control in vivo in xenografts derived from acquired resistant models.
    explanation: >-
      Xenograft validation supports preclinical cell-cycle cotargeting, with kinase-specific responses.
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Acquired RAS(ON) Inhibitor Resistance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Under the specified RAS-inhibitor exposure, this route can sustain tumor growth or reduce target
      inhibition. Source and regimen restrictions apply.
    evidence:
    - reference: PMID:41959066
      reference_title: Targeting Distinct Cell Cycle Nodes Overcomes KRAS/RAS Inhibitor Resistance.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: While these pathways can be broadly inhibited using the pan-RAS-ON inhibitor RMC-6236, cells remained capable of developing acquired resistance where cell proliferation is uncoupled from RAS signaling.
      explanation: >-
        Preprint directly models RMC-6236 resistance in cellular systems.
    - reference: PMID:41959066
      reference_title: Targeting Distinct Cell Cycle Nodes Overcomes KRAS/RAS Inhibitor Resistance.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Finally, concurrent inhibition of KRAS with either CDK4/6 or CDK2 yields durable tumor control in vivo in xenografts derived from acquired resistant models.
      explanation: >-
        Xenograft validation supports preclinical cell-cycle cotargeting, with kinase-specific responses.
    hypothesis_groups:
    - ras_on_inhibitor_acquired_resistance
- name: Acquired RAS(ON) Inhibitor Resistance
  biological_scale: CELLULAR
  description: >-
    Daraxonrasib can initially control PDAC and subsequently lose efficacy through heterogeneous
    resistance routes. An August 2026 study profiled 44 patients with response or stable disease
    lasting more than three months followed by progression: 59% had treatment-emergent RAS-pathway
    genomic alterations, including KRAS amplification in 36%. Mutant-allele identity was inferred from
    variant-allele-frequency ratios by an exploratory method, not directly confirmed in all cases.
    These selected-cohort findings establish patient mechanisms but not universal resistance or population-wide route frequencies.
    Median progression-free survival alone cannot distinguish acquired resistance, primary nonresponse
    and death. Non-genomic, tissue-specific and low-shedding routes remain incompletely captured.
  evidence:
  - reference: PMID:42581230
    reference_title: Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we report mechanisms of acquired resistance to daraxonrasib monotherapy observed through targeted sequencing of over 800 genes in paired pretreatment and end of treatment circulating tumor DNA samples from 44 patients in the phase 1/2 clinical trial.
    explanation: >-
      August 2026 paired clinical sequencing supersedes the July reports and earlier assessment claim
      that no longitudinal clinical characterization was available.
  - reference: PMID:42581230
    reference_title: Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26 of 44; 59%) of these patients, including, most notably, mutant KRAS amplifications in one-third (16 of 44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4 of 44; 9%), MAPK (11 of 44; 25%) and PI3K (4 of 44; 9%) pathways.
    explanation: >-
      Frequencies apply to 44 profiled patients with prior disease control followed by progression,
      not all treated PDAC patients; categories overlap. Mutant-allele attribution from ctDNA is
      exploratory and unconfirmed, as specified in Supplementary Table 3.
  - reference: PMID:42581230
    reference_title: Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Notably, no acquired secondary KRAS mutations were observed, distinct from resistance profiles of mutant-selective KRAS G12C(OFF) inhibitors.
    explanation: >-
      No secondary KRAS mutations were found in this selected PDAC cohort; this is not proof that
      such mutations are impossible.
  - reference: PMID:42090791
    reference_title: Daraxonrasib in Previously Treated Advanced RAS-Mutated Pancreatic Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Among the 38 patients with RAS G12, G13, or Q61 mutations, 29% (95% CI, 15 to 46) had an objective response. The median duration of response was 8.2 months (95% CI, 3.8 to 8.8), with median values of 8.1 months for progression-free survival and 15.6 months for overall survival.
    explanation: >-
      Quantifies the primary-nonresponse term in this node's description. Responses are finite, which
      is the acquired-resistance signal, but fewer than a third of treated patients had an objective
      response at all, so progression on daraxonrasib cannot be read as escape from an established
      response across the treated population.
- name: On-Target RAS Reactivation and KRAS Amplification
  mechanism_confidence: PROVISIONAL
  biological_scale: MOLECULAR
  description: >-
    Increased mutant KRAS dosage can attenuate daraxonrasib suppression and restore RAS-pathway
    output in PDAC models. Paired ctDNA detected emergent KRAS amplification in 16/44 profiled PDAC
    patients after initial disease control. Assignment to the pre-existing mutant allele was inferred
    from variant-allele-frequency ratios; the supplementary table explicitly calls this exploratory
    and unconfirmed, rather than direct allele phasing in all cases. Engineered and selected PDAC
    models provide functional corroboration of mutant KRAS dosage. Secondary KRAS mutations were
    absent from the 44 PDAC cases and selected PDAC resistance models, while an engineered Ba/F3
    deep mutational scan identified resistance-conferring second-site variants in a different context.
  evidence:
  - reference: PMID:42581230
    reference_title: Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26 of 44; 59%) of these patients, including, most notably, mutant KRAS amplifications in one-third (16 of 44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4 of 44; 9%), MAPK (11 of 44; 25%) and PI3K (4 of 44; 9%) pathways.
    explanation: >-
      Frequencies apply to 44 profiled patients with prior disease control followed by progression,
      not all treated PDAC patients; categories overlap. Mutant-allele attribution from ctDNA is
      exploratory and unconfirmed, as specified in Supplementary Table 3.
  - reference: PMID:42581230
    reference_title: Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Method is exploratory, and allele amplification is not confirmed.
    explanation: >-
      Supplementary Table 3 qualifies mutant-versus-wild-type assignment from relative variant allele
      frequencies. This limitation does not negate the observed 16/44 KRAS amplification calls.
  - reference: PMID:42581230
    reference_title: Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: To corroborate these clinical findings, we found, or mechanistically established, concordant mechanisms of daraxonrasib resistance in human and murine preclinical models of PDAC, including mutant KRAS and MYC amplification and RTK upregulation, with these alterations guiding various combination therapy concepts.
    explanation: >-
      Preclinical perturbation corroborates selected clinical candidate routes; it does not establish
      causality for every observed co-alteration.
  downstream:
  - target: Acquired RAS(ON) Inhibitor Resistance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Under the specified RAS-inhibitor exposure, this route can sustain tumor growth or reduce target
      inhibition. Source and regimen restrictions apply.
    evidence:
    - reference: PMID:42581230
      reference_title: Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26 of 44; 59%) of these patients, including, most notably, mutant KRAS amplifications in one-third (16 of 44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4 of 44; 9%), MAPK (11 of 44; 25%) and PI3K (4 of 44; 9%) pathways.
      explanation: >-
        Frequencies apply to 44 profiled patients with prior disease control followed by progression,
        not all treated PDAC patients; categories overlap. Mutant-allele attribution from ctDNA is
        exploratory and unconfirmed, as specified in Supplementary Table 3.
    - reference: PMID:42581230
      reference_title: Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: To corroborate these clinical findings, we found, or mechanistically established, concordant mechanisms of daraxonrasib resistance in human and murine preclinical models of PDAC, including mutant KRAS and MYC amplification and RTK upregulation, with these alterations guiding various combination therapy concepts.
      explanation: >-
        Preclinical perturbation corroborates selected clinical candidate routes; it does not establish
        causality for every observed co-alteration.
    hypothesis_groups:
    - ras_on_inhibitor_acquired_resistance
  notes: >-
    No causal edge from initiating KRAS activation to acquired KRAS amplification is asserted.
    Amplification emerged in selected tumors under RAS-inhibitor treatment, with separate
    preclinical perturbation evidence for resistance; the clinical paired-ctDNA cohort does not
    show that KRAS activation alone generates this adaptation. The resistance branch is connected
    to tumor signaling through the experimentally tested RAS-targeting combination.
- name: RTK and Feedback Pathway Reactivation
  mechanism_confidence: PROVISIONAL
  biological_scale: MOLECULAR
  description: >-
    RTK signaling can contribute to daraxonrasib resistance in particular PDAC contexts. The paired
    44-patient study found emergent RTK alterations in 4/44, with HER2-upregulated resistant models
    providing functional support. A separate preprint identified EGFR/wild-type-RAS activation in
    KRAS-G12R models and one patient who progressed after ten months. G12D cyclophilin-A loss is
    a distinct route. Earlier MEK or G12C-selective-inhibitor studies are contextual analogies and
    do not establish universal sufficiency against multiselective inhibition.
  evidence:
  - reference: PMID:42581230
    reference_title: Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26 of 44; 59%) of these patients, including, most notably, mutant KRAS amplifications in one-third (16 of 44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4 of 44; 9%), MAPK (11 of 44; 25%) and PI3K (4 of 44; 9%) pathways.
    explanation: >-
      Frequencies apply to 44 profiled patients with prior disease control followed by progression,
      not all treated PDAC patients; categories overlap. Mutant-allele attribution from ctDNA is
      exploratory and unconfirmed, as specified in Supplementary Table 3.
  - reference: PMID:42465401
    reference_title: 'Overcoming Daraxonrasib Resistance: Allele-Specific Mechanisms Guide Salvage Therapy in Pancreatic Cancer.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: KRAS G12R is marked by its inability to transactivate RAS WT , and it was observed that daraxonrasib resistant KRAS G12R PDAC cells utilize EGFR/RAS WT -GTP signaling as the dominant adaptive route.
    explanation: >-
      Preprint supports an allele-specific cellular route; it should not be generalized to all KRAS
      alleles.
  - reference: PMID:42465401
    reference_title: 'Overcoming Daraxonrasib Resistance: Allele-Specific Mechanisms Guide Salvage Therapy in Pancreatic Cancer.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a KRAS G12R PDAC patient who progressed after 10 months on daraxonrasib showed intratumoral EGFR/RAS WT activation
    explanation: >-
      One-patient molecular observation, supplemented by ex-vivo toroid modeling; subsequent multiagent
      salvage cannot isolate trametinib benefit.
  - reference: PMID:25736685
    reference_title: Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Proteomic analysis evidenced that MEK1 inhibition was accompanied by a sustained activation of the PI3K-AKT-MTOR pathway and by the activation of AXL, PDGFRa, and HER1-2 receptor tyrosine kinases (RTK) expressed in a large proportion of human PDAC samples analyzed.
    explanation: >-
      Grounds the contextual analogy this node's description invokes, in PDAC rather than in another
      tumour type: in an inducible KRAS-G12D mouse PDAC model, MEK1 inhibition reactivates AXL,
      PDGFRa and HER1-2 alongside sustained PI3K-AKT-mTOR signaling. The blockade is partial, MEK
      only, so it does not establish sufficiency of RTK reactivation against multiselective RAS(ON)
      inhibition.
  downstream:
  - target: Acquired RAS(ON) Inhibitor Resistance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Under the specified RAS-inhibitor exposure, this route can sustain tumor growth or reduce target
      inhibition. Source and regimen restrictions apply.
    evidence:
    - reference: PMID:42581230
      reference_title: Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26 of 44; 59%) of these patients, including, most notably, mutant KRAS amplifications in one-third (16 of 44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4 of 44; 9%), MAPK (11 of 44; 25%) and PI3K (4 of 44; 9%) pathways.
      explanation: >-
        Frequencies apply to 44 profiled patients with prior disease control followed by progression,
        not all treated PDAC patients; categories overlap. Mutant-allele attribution from ctDNA is
        exploratory and unconfirmed, as specified in Supplementary Table 3.
    - reference: PMID:42465401
      reference_title: 'Overcoming Daraxonrasib Resistance: Allele-Specific Mechanisms Guide Salvage Therapy in Pancreatic Cancer.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: KRAS G12R is marked by its inability to transactivate RAS WT , and it was observed that daraxonrasib resistant KRAS G12R PDAC cells utilize EGFR/RAS WT -GTP signaling as the dominant adaptive route.
      explanation: >-
        Preprint supports an allele-specific cellular route; it should not be generalized to all
        KRAS alleles.
    - reference: PMID:42465401
      reference_title: 'Overcoming Daraxonrasib Resistance: Allele-Specific Mechanisms Guide Salvage Therapy in Pancreatic Cancer.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: a KRAS G12R PDAC patient who progressed after 10 months on daraxonrasib showed intratumoral EGFR/RAS WT activation
      explanation: >-
        One-patient molecular observation, supplemented by ex-vivo toroid modeling; subsequent multiagent
        salvage cannot isolate trametinib benefit.
    hypothesis_groups:
    - ras_on_inhibitor_acquired_resistance
- name: Adaptive mTOR and JUN-AP1 Transcriptional Program
  mechanism_confidence: PROVISIONAL
  biological_scale: CELLULAR
  description: >-
    CRISPR screens identify mTOR and JUN as convergent mediators of resistance to MAPK-pathway inhibitor
    combinations. In PDAC cells, JUN overexpression supported resistance to SHP2 plus RMC-6236; in-vivo
    MAP2K4 rescue used SHP2 plus ERK inhibition. The combination-specific evidence should not be
    recast as patient-level daraxonrasib monotherapy resistance. A separate RMC-7977 mouse study
    identified focal Jun gain in one resistant tumor.
  evidence:
  - reference: PMID:41572361
    reference_title: CRISPR knockout screens reveal JUN as the master mediator of resistance to MAPK inhibition in KRAS-mutant pancreatic cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Through unbiased CRISPR-based screenings, we identified mTOR and JUN hyperactivation as interconnected mechanisms that overcome MAPK suppression.
    explanation: >-
      CRISPR and follow-up cellular experiments support the combination-treatment scope.
  - reference: PMID:41572361
    reference_title: CRISPR knockout screens reveal JUN as the master mediator of resistance to MAPK inhibition in KRAS-mutant pancreatic cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Alterations in the PI3K/AKT/mTOR and JUN pathways can induce resistance to multiple combinations of MAPK pathway inhibitors
    explanation: >-
      The study conclusion explicitly concerns combinations, not a proven universal monotherapy escape
      mechanism.
  downstream:
  - target: Acquired RAS(ON) Inhibitor Resistance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Under the specified RAS-inhibitor exposure, this route can sustain tumor growth or reduce target
      inhibition. Source and regimen restrictions apply.
    evidence:
    - reference: PMID:41572361
      reference_title: CRISPR knockout screens reveal JUN as the master mediator of resistance to MAPK inhibition in KRAS-mutant pancreatic cancer.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Through unbiased CRISPR-based screenings, we identified mTOR and JUN hyperactivation as interconnected mechanisms that overcome MAPK suppression.
      explanation: >-
        CRISPR and follow-up cellular experiments support the combination-treatment scope.
    - reference: PMID:41572361
      reference_title: CRISPR knockout screens reveal JUN as the master mediator of resistance to MAPK inhibition in KRAS-mutant pancreatic cancer.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Alterations in the PI3K/AKT/mTOR and JUN pathways can induce resistance to multiple combinations of MAPK pathway inhibitors
      explanation: >-
        The study conclusion explicitly concerns combinations, not a proven universal monotherapy
        escape mechanism.
    hypothesis_groups:
    - ras_on_inhibitor_acquired_resistance
- name: Mitochondrial Remodeling and Ferroptosis Vulnerability
  mechanism_confidence: PROVISIONAL
  biological_scale: CELLULAR
  description: >-
    Dual SHP2-MEK inhibition produces persistent mitochondrial changes and lipid-peroxide-defense
    dependency in PDAC models, with confirmation under direct RAS targeting. Sensitivity to GPX4
    disruption is an exploitable treatment-induced vulnerability; it does not mean ferroptosis is
    already increased or that this state itself causes clinical daraxonrasib resistance. The primary
    intervention and model context are retained.
  evidence:
  - reference: PMID:41545339
    reference_title: Vertical RAS pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We found that dual SHP2/mitogen-activated protein kinase kinase (MEK1/2) inhibition induces major alterations in mitochondrial mass and function, impacts reactive oxygen species (ROS) homeostasis and triggers lipid peroxidase dependency.
    explanation: >-
      The primary experiment concerns vertical SHP2-MEK blockade.
- name: MYC Amplification-Driven RAS-Independent Proliferation
  mechanism_confidence: PROVISIONAL
  biological_scale: MOLECULAR
  description: >-
    RMC-7977-resistant KPC tumors frequently gained Myc copies while maintaining ERK suppression.
    YAP-TEAD-dependent transcriptional output accompanied resistance, and TEAD cotargeting restored
    sensitivity in vitro. The subsequent daraxonrasib clinical study detected MYC amplification in
    one patient together with KRAS amplification and corroborated MYC-related resistance in models.
    These data support a bypass route without proving that all MYC gain is independent of RAS or
    that TEAD combinations benefit patients.
  evidence:
  - reference: PMID:38588697
    reference_title: Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro.
    explanation: >-
      Primary 2024 RMC-7977 study supplies stronger support than the systematic review cited by OpenScientist.
  - reference: PMID:42581230
    reference_title: Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We also observed truncating mutations in NF1 (2 of 44; 4%), KEAP1 (2 of 44; 4%), a PTPN11 mutation or MYC amplification in one patient each (1 of 44; 2%).
    explanation: >-
      MYC alteration occurs in one selected clinical case; co-occurrence and small numbers limit
      attribution.
  genes:
  - preferred_term: MYC
    term:
      id: hgnc:7553
      label: MYC
  - preferred_term: YAP1
    term:
      id: hgnc:16262
      label: YAP1
  downstream:
  - target: Acquired RAS(ON) Inhibitor Resistance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Under the specified RAS-inhibitor exposure, this route can sustain tumor growth or reduce target
      inhibition. Source and regimen restrictions apply.
    evidence:
    - reference: PMID:38588697
      reference_title: Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro.
      explanation: >-
        Primary 2024 RMC-7977 study supplies stronger support than the systematic review cited by
        OpenScientist.
    - reference: PMID:42581230
      reference_title: Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We also observed truncating mutations in NF1 (2 of 44; 4%), KEAP1 (2 of 44; 4%), a PTPN11 mutation or MYC amplification in one patient each (1 of 44; 2%).
      explanation: >-
        MYC alteration occurs in one selected clinical case; co-occurrence and small numbers limit
        attribution.
    hypothesis_groups:
    - ras_on_inhibitor_acquired_resistance
- name: Myeloid Suppression Relief and CD8 Effector Infiltration
  biological_scale: TISSUE
  description: >-
    MRTX1133 and RAS(ON) multiselective inhibitors can reduce suppressive myeloid subsets and increase
    effector lymphocytes in immunocompetent PDAC models. Total macrophage abundance can increase
    while state composition changes; myeloid remodeling is not equivalent to depletion of every myeloid
    cell. The direction and durability of individual populations vary by agent, model and time.
  cell_types:
  - preferred_term: CD8-positive effector T cell
    modifier: INCREASED
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  evidence:
  - reference: PMID:40057911
    reference_title: T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In this study, we report that RAS(ON) multi-selective inhibition led to rapid and profound PDAC regressions in immunocompetent mice, decreasing myeloid cells and increasing T cells and macrophages in the tumor microenvironment.
    explanation: >-
      Direct PDAC evidence was omitted from the immune report despite being cited in the resistance
      report.
  - reference: PMID:37625401
    reference_title: KRAS(G12D) inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8(+) T cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: MRTX1133 reverses early PDAC growth, increases intratumoral CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer-associated fibroblasts.
    explanation: >-
      Final peer-reviewed MRTX1133 paper; its preprint PMID36824971 is not independent replication.
  downstream:
  - target: Immunosuppressive TME Reversibility under RAS(ON) Inhibition
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The observed treatment-induced change contributes to immune recognition or immune-dependent
      tumor control in the specified model.
    evidence:
    - reference: PMID:40057911
      reference_title: T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: In this study, we report that RAS(ON) multi-selective inhibition led to rapid and profound PDAC regressions in immunocompetent mice, decreasing myeloid cells and increasing T cells and macrophages in the tumor microenvironment.
      explanation: >-
        Direct PDAC evidence was omitted from the immune report despite being cited in the resistance
        report.
    - reference: PMID:37625401
      reference_title: KRAS(G12D) inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8(+) T cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: MRTX1133 reverses early PDAC growth, increases intratumoral CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer-associated fibroblasts.
      explanation: >-
        Final peer-reviewed MRTX1133 paper; its preprint PMID36824971 is not independent replication.
    hypothesis_groups:
    - ras_on_inhibition_immune_tme_remodeling
- name: Tumor-Cell FAS Induction and CD8-Mediated Killing
  mechanism_confidence: PROVISIONAL
  biological_scale: CELLULAR
  description: >-
    KRAS-G12D inhibition by MRTX1133 induces FAS in malignant cells and patient-derived organoids,
    permitting CD8-mediated killing in PDAC models. This is drug- and model-specific evidence; the
    original citation to the preprint has been replaced with the final paper. CDK8-dependent FAS
    suppression can later oppose this response.
  evidence:
  - reference: PMID:37625401
    reference_title: KRAS(G12D) inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8(+) T cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Mechanistically, inhibition of KRASG12D in advanced PDAC and human patient derived organoids induces FAS expression in cancer cells and facilitates CD8+ T cell-mediated death.
    explanation: >-
      The final primary report directly supports FAS induction and killing, including human organoid
      experiments.
  downstream:
  - target: Immunosuppressive TME Reversibility under RAS(ON) Inhibition
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The observed treatment-induced change contributes to immune recognition or immune-dependent
      tumor control in the specified model.
    evidence:
    - reference: PMID:37625401
      reference_title: KRAS(G12D) inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8(+) T cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Mechanistically, inhibition of KRASG12D in advanced PDAC and human patient derived organoids induces FAS expression in cancer cells and facilitates CD8+ T cell-mediated death.
      explanation: >-
        The final primary report directly supports FAS induction and killing, including human organoid
        experiments.
    hypothesis_groups:
    - ras_on_inhibition_immune_tme_remodeling
- name: Antigen Presentation Restoration
  mechanism_confidence: PROVISIONAL
  biological_scale: CELLULAR
  description: >-
    RMC-7977 increased MHC-I on residual malignant cells in a syngeneic PDAC model. This is direct
    evidence for a RAS(ON)-associated antigen-presentation change in PDAC, although the relative
    mediation by autophagy, FAK, interferon signaling and tumor selection remains unresolved. NSCLC
    daraxonrasib-elironrasib results are supplementary cross-cancer evidence, not the sole anchor.
  biological_processes:
  - preferred_term: antigen processing and presentation
    modifier: INCREASED
    term:
      id: GO:0019882
      label: antigen processing and presentation
  evidence:
  - reference: PMID:40057911
    reference_title: T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: the tumor cells that remained exhibited increased expression of MHC class I
    explanation: >-
      Flow-cytometric on-treatment finding in 6419c5 PDAC tumors after RMC-7977; this does not establish
      the precise molecular mediator.
  downstream:
  - target: Immunosuppressive TME Reversibility under RAS(ON) Inhibition
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The observed treatment-induced change contributes to immune recognition or immune-dependent
      tumor control in the specified model.
    evidence:
    - reference: PMID:40057911
      reference_title: T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: the tumor cells that remained exhibited increased expression of MHC class I
      explanation: >-
        Flow-cytometric on-treatment finding in 6419c5 PDAC tumors after RMC-7977; this does not
        establish the precise molecular mediator.
    hypothesis_groups:
    - ras_on_inhibition_immune_tme_remodeling
- name: USP20 Cholesterol-Metabolism CD8 Exhaustion Checkpoint
  mechanism_confidence: PROVISIONAL
  biological_scale: CELLULAR
  description: >-
    KRAS-G12D induces EGR1-USP20, stabilizing HMG-CoA reductase and promoting cholesterol metabolism
    associated with CD8 exhaustion. KRAS inhibition or cholesterol blockade induces compensatory
    ULK1-associated autophagy; USP20 also stabilizes ULK1. This is a two-arm metabolic and survival
    mechanism. MRTX1133 plus USP20 inhibition and PD-1 blockade regressed tumors in preclinical models,
    but human tissue profiling is not evidence of clinical combination efficacy.
  evidence:
  - reference: PMID:42392864
    reference_title: USP20 promotes CD8(+) T cell exhaustion and impairs KRAS(G12D) inhibitor efficacy by orchestrating cholesterol metabolism and autophagy in pancreatic cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Mechanistically, KRASG12D transcriptionally upregulated USP20 via EGR1, which simultaneously deubiquitinated and stabilised 3-hydroxy-3-methylglutaryl-CoA reductase and ULK1, thereby orchestrating cholesterol metabolism and autophagy-associated survival.
    explanation: >-
      Mechanistic preclinical experiments relate USP20 to cholesterol and autophagy; the cohort provides
      human-tissue context.
  - reference: PMID:42392864
    reference_title: USP20 promotes CD8(+) T cell exhaustion and impairs KRAS(G12D) inhibitor efficacy by orchestrating cholesterol metabolism and autophagy in pancreatic cancer.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In preclinical PDAC models, triple therapy with GSK2643943A, MRTX1133 and anti-PD-1 elicited a robust therapeutic response and induced significant tumour regression.
    explanation: >-
      Mouse combination activity remains investigational.
  downstream:
  - target: Immune Evasion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cholesterol-associated dysfunction contributes to CD8 exhaustion.
    evidence:
    - reference: PMID:42392864
      reference_title: USP20 promotes CD8(+) T cell exhaustion and impairs KRAS(G12D) inhibitor efficacy by orchestrating cholesterol metabolism and autophagy in pancreatic cancer.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Mechanistically, KRASG12D transcriptionally upregulated USP20 via EGR1, which simultaneously deubiquitinated and stabilised 3-hydroxy-3-methylglutaryl-CoA reductase and ULK1, thereby orchestrating cholesterol metabolism and autophagy-associated survival.
      explanation: >-
        Mechanistic preclinical experiments relate USP20 to cholesterol and autophagy; the cohort
        provides human-tissue context.
    - reference: PMID:42392864
      reference_title: USP20 promotes CD8(+) T cell exhaustion and impairs KRAS(G12D) inhibitor efficacy by orchestrating cholesterol metabolism and autophagy in pancreatic cancer.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: In preclinical PDAC models, triple therapy with GSK2643943A, MRTX1133 and anti-PD-1 elicited a robust therapeutic response and induced significant tumour regression.
      explanation: >-
        Mouse combination activity remains investigational.
    hypothesis_groups:
    - ras_on_inhibition_immune_tme_remodeling
  - target: Autophagy-Lysosome Growth Support
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      USP20 stabilizes ULK1 and supports compensatory autophagy under KRAS-G12D or cholesterol inhibition.
    evidence:
    - reference: PMID:42392864
      reference_title: USP20 promotes CD8(+) T cell exhaustion and impairs KRAS(G12D) inhibitor efficacy by orchestrating cholesterol metabolism and autophagy in pancreatic cancer.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Mechanistically, KRASG12D transcriptionally upregulated USP20 via EGR1, which simultaneously deubiquitinated and stabilised 3-hydroxy-3-methylglutaryl-CoA reductase and ULK1, thereby orchestrating cholesterol metabolism and autophagy-associated survival.
      explanation: >-
        Mechanistic preclinical experiments relate USP20 to cholesterol and autophagy; the cohort
        provides human-tissue context.
    intermediate_mechanisms:
    - ULK1 stabilization
    hypothesis_groups:
    - ras_on_inhibition_immune_tme_remodeling
- name: CDK8-CXCL2 Adaptive Immune Reversal
  mechanism_confidence: PROVISIONAL
  biological_scale: CELLULAR
  description: >-
    Long-term MRTX1133 treatment can reverse early immune infiltration through CDK8-associated CXCL2
    secretion and FAS suppression. CDK8 perturbation restores immune control in those PDAC models.
    Daraxonrasib-resistant PDX tumors also show CDK8 upregulation, but this does not establish the
    entire temporal CXCL2/FAS immune circuit under daraxonrasib or in patients.
  evidence:
  - reference: PMID:42436354
    reference_title: CDK8 remodels the tumor microenvironment and promotes resistance to KRAS(G12D) inhibitors and daraxonrasib in PDAC.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: CDK8 imparts this resistance via induction of CXCL2 chemokine secretion, inhibition of FAS expression, and remodeling of the TME to promote immune evasion.
    explanation: >-
      The mechanistic immune reversal was tested chiefly during MRTX1133 treatment.
  - reference: PMID:42436354
    reference_title: CDK8 remodels the tumor microenvironment and promotes resistance to KRAS(G12D) inhibitors and daraxonrasib in PDAC.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: 'We also provide evidence of CDK8 upregulation in PDX tumors resistant to inhibitors selective for RAS(ON) and RASG12D(ON): daraxonrasib and zoldonrasib, respectively'
    explanation: >-
      PDX expression supports a shared candidate node, without proving drug-specific immune mediation.
  downstream:
  - target: Immune Evasion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Under prolonged MRTX1133 exposure, CXCL2 and FAS changes restore immune suppression.
    evidence:
    - reference: PMID:42436354
      reference_title: CDK8 remodels the tumor microenvironment and promotes resistance to KRAS(G12D) inhibitors and daraxonrasib in PDAC.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: CDK8 imparts this resistance via induction of CXCL2 chemokine secretion, inhibition of FAS expression, and remodeling of the TME to promote immune evasion.
      explanation: >-
        The mechanistic immune reversal was tested chiefly during MRTX1133 treatment.
    intermediate_mechanisms:
    - CXCL2 secretion
    - Reduced FAS-mediated susceptibility to immune killing
    hypothesis_groups:
    - ras_on_inhibition_immune_tme_remodeling
    - ras_on_inhibitor_acquired_resistance
- name: Regulatory T-Cell Recruitment after KRAS Inhibition
  mechanism_confidence: PROVISIONAL
  description: >-
    An August 2026 PDAC study found that MRTX1133 or daraxonrasib recruits regulatory as well as
    effector and exhausted T cells. In its models, CTLA-4 blockade reprogrammed effector Tregs, reduced
    CD8 exhaustion and supported tertiary lymphoid structures. Other checkpoint combinations were
    less effective. This contrasts with a different RMC-7977 model where the CD4 increase was not
    attributable to FoxP3-positive Tregs, so generalized Treg relief is not supported.
  evidence:
  - reference: DOI:10.1038/s41467-026-75960-3
    reference_title: Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Here, we demonstrate that Kras* targeting using MRTX1133 or Daraxonrasib recruits diverse T-cell infiltrates, including regulatory (Tregs), effector and exhausted T cells into the PDAC microenvironment.
    explanation: >-
      Newer mouse PDAC evidence replaces the unsupported positive Treg-relief node.
  - reference: PMID:40057911
    reference_title: T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: the increase in CD4+ T cells upon RMC-7977 treatment was not attributable to this population
    explanation: >-
      In this separate model the CD4 expansion did not reflect FoxP3-positive Tregs, illustrating
      model dependence.
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
- name: IL6-CAF and Myeloid Rebound after SOS1-MEK Inhibition
  mechanism_confidence: PROVISIONAL
  description: >-
    SOS1 plus MEK blockade increased CD8 infiltration but also generated IL6-positive inflammatory
    CAFs, M2-like macrophages and poorer dendritic-cell function in KPCY models. CD40 agonism reactivated
    myeloid cells and enabled durable checkpoint combinations. This qualifies a uniformly beneficial
    RAS-inhibition model but is not direct daraxonrasib evidence.
  evidence:
  - reference: PMID:38727236
    reference_title: Reshaping the Tumor Microenvironment of KRASG12D Pancreatic Ductal Adenocarcinoma with Combined SOS1 and MEK Inhibition for Improved Immunotherapy Response.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: revealed an increase in inflammatory cancer-associated fibroblasts (iCAF), M2 macrophages, and a decreased dendritic cell (DC) quality
    explanation: >-
      Single-cell and perturbation work establishes a counter-regulatory microenvironment under SOS1-MEK
      blockade.
  downstream:
  - target: Immune Evasion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Stromal and myeloid adaptation can limit the benefit of initial T-cell entry.
    evidence:
    - reference: PMID:38727236
      reference_title: Reshaping the Tumor Microenvironment of KRASG12D Pancreatic Ductal Adenocarcinoma with Combined SOS1 and MEK Inhibition for Improved Immunotherapy Response.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: revealed an increase in inflammatory cancer-associated fibroblasts (iCAF), M2 macrophages, and a decreased dendritic cell (DC) quality
      explanation: >-
        Single-cell and perturbation work establishes a counter-regulatory microenvironment under
        SOS1-MEK blockade.
    hypothesis_groups:
    - ras_on_inhibition_immune_tme_remodeling
- name: Basal-State GM-CSF Immunosuppressive Circuit
  mechanism_confidence: PROVISIONAL
  description: >-
    Basal malignant cells can organize tumor-maintaining fibroblast, macrophage and cytokine states.
    Lineage tracing found greater plasticity of basal than classical cells in autochthonous mouse
    PDAC. Basal-state ablation, and separately basal-cell GM-CSF knockout, reprogrammed the stroma
    and recruited cytotoxic lymphocytes. This establishes a causal circuit in these models while
    leaving human state-targeting efficacy unresolved.
  evidence:
  - reference: PMID:42523238
    reference_title: The basal cell state maintains pancreatic cancers by controlling an immunosuppressive circuit.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Knockout of a single cytokine, GM-CSF, specifically in basal cells recapitulated macrophage repolarization and lymphocyte recruitment observed upon basal state ablation and shrank tumors.
    explanation: >-
      Basal-cell-specific genetic perturbation establishes an immune-organizing GM-CSF role in mouse
      PDAC. Human prognostic association does not establish the same intervention effect.
  genes:
  - preferred_term: CSF2
    term:
      id: hgnc:2434
      label: CSF2
  downstream:
  - target: Immune Evasion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Basal-cell GM-CSF maintains an immunosuppressive tumor ecosystem in autochthonous mouse PDAC.
    evidence:
    - reference: PMID:42523238
      reference_title: The basal cell state maintains pancreatic cancers by controlling an immunosuppressive circuit.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Knockout of a single cytokine, GM-CSF, specifically in basal cells recapitulated macrophage repolarization and lymphocyte recruitment observed upon basal state ablation and shrank tumors.
      explanation: >-
        Basal-cell-specific genetic perturbation establishes an immune-organizing GM-CSF role in
        mouse PDAC. Human prognostic association does not establish the same intervention effect.
- name: Pancreatic Exocrine Functional Loss
  description: >-
    Tumor-associated obstruction and loss of functional pancreatic tissue can impair digestive enzyme
    delivery. The resulting maldigestion contributes to nutritional loss; this process also occurs
    after pancreatic surgery. Clinical prevalence varies with stage, location and testing method.
  evidence:
  - reference: PMID:32631175
    reference_title: 'Pancreatic exocrine insufficiency and pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer: A systematic review and meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The pooled prevalence of pancreatic exocrine insufficiency in advanced pancreatic cancer was 72% (95% confidence interval: 55-86%)'
    explanation: >-
      Meta-analysis supports substantial exocrine insufficiency specifically in advanced pancreatic
      cancer; heterogeneity and tumor location limit generalization to all PDAC.
  downstream:
  - target: Exocrine Pancreatic Insufficiency
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Loss of digestive enzyme delivery produces clinical pancreatic exocrine insufficiency.
    evidence:
    - reference: PMID:32631175
      reference_title: 'Pancreatic exocrine insufficiency and pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer: A systematic review and meta-analysis.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'The pooled prevalence of pancreatic exocrine insufficiency in advanced pancreatic cancer was 72% (95% confidence interval: 55-86%)'
      explanation: >-
        Meta-analysis supports substantial exocrine insufficiency specifically in advanced pancreatic
        cancer; heterogeneity and tumor location limit generalization to all PDAC.
  - target: Weight Loss
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Maldigestion is one contributor to weight loss in advanced pancreatic cancer.
    evidence:
    - reference: PMID:32631175
      reference_title: 'Pancreatic exocrine insufficiency and pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer: A systematic review and meta-analysis.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Pancreatic exocrine insufficiency is one of the causes of malnutrition and weight loss in these patients.
      explanation: >-
        Clinical synthesis identifies this contribution without attributing all weight loss to pancreatic
        insufficiency.
- name: Adaptive CD24 Antiphagocytic Signaling
  mechanism_confidence: PROVISIONAL
  description: >-
    In KRAS-G12C-driven mouse PDAC, selective KRAS inhibition upregulated the CD24 antiphagocytic
    signal despite an inflamed microenvironment. CD24 blockade increased macrophage phagocytosis
    and sensitized tumors; related findings occurred in G12D PDAC. The preprint and final paper report
    the same work. This is a plausible immune-adaptation route whose relevance to clinical daraxonrasib
    progression remains unproven.
  evidence:
  - reference: PMID:40966362
    reference_title: KRAS Inhibition Activates an Actionable CD24 "Do Not Eat Me" Signal in Pancreatic Cancer.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment.
    explanation: >-
      Functional antibody perturbation supports CD24-mediated adaptation in G12C/G12D-selective-inhibitor
      PDAC models, not a proven clinical daraxonrasib-resistance route.
  genes:
  - preferred_term: CD24
    term:
      id: hgnc:1645
      label: CD24
  downstream:
  - target: Immune Evasion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Induced CD24 reduces macrophage-mediated tumor-cell clearance in selective-KRAS-inhibitor models.
    evidence:
    - reference: PMID:40966362
      reference_title: KRAS Inhibition Activates an Actionable CD24 "Do Not Eat Me" Signal in Pancreatic Cancer.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment.
      explanation: >-
        Functional antibody perturbation supports CD24-mediated adaptation in G12C/G12D-selective-inhibitor
        PDAC models, not a proven clinical daraxonrasib-resistance route.
    hypothesis_groups:
    - ras_on_inhibitor_acquired_resistance
    - ras_on_inhibition_immune_tme_remodeling
- name: Senescent Myofibroblast Immunosuppression
  mechanism_confidence: PROVISIONAL
  description: >-
    Senescent myofibroblastic CAFs accumulate near tumor ducts and during PDAC progression. Genetic
    or pharmacologic depletion of senescent stromal cells in mouse models reduced macrophage-associated
    immune suppression and improved chemotherapy responsiveness. Human tissue identifies the state,
    but clinical senolytic efficacy is not established.
  evidence:
  - reference: DOI:10.1158/2159-8290.CD-23-0428
    reference_title: Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy.
    explanation: >-
      Mouse senescent-stroma perturbation supports a specific promoting CAF state, complementary
      to tumor-restraining fibroblast programs.
  downstream:
  - target: Immune Evasion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Senescent stromal programs maintain macrophage-mediated immune suppression in PDAC models.
    evidence:
    - reference: DOI:10.1158/2159-8290.CD-23-0428
      reference_title: Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy.
      explanation: >-
        Mouse senescent-stroma perturbation supports a specific promoting CAF state, complementary
        to tumor-restraining fibroblast programs.
histopathology:
- name: Malignant Glandular Differentiation
  finding_term:
    preferred_term: Glandular Differentiation
    term:
      id: NCIT:C43573
      label: Glandular Differentiation
  description: >-
    Infiltrative malignant epithelial glands with ductal differentiation; differentiation can vary
    and this morphology does not establish an exclusively ductal cell of origin.
- name: Desmoplastic Stroma
  finding_term:
    preferred_term: desmoplastic stroma
    term:
      id: NCIT:C36178
      label: Fibrotic Stroma Formation
  description: >-
    Dense collagen-rich fibrotic stroma surrounding malignant glands is a defining
    histopathologic feature of PDAC.
  evidence:
  - reference: PMID:30366930
    reference_title: IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Here, we use organoid and mouse models to identify TGFβ and IL1 as tumor-secreted ligands that promote CAF heterogeneity.
    explanation: >-
      Tumor-secreted signals establish heterogeneous stromal responses.
phenotypes:
- category: Neoplastic
  name: Pancreatic Adenocarcinoma
  frequency: OBLIGATE
  description: >-
    Malignant pancreatic epithelial neoplasm with ductal differentiation. Ductal morphology does
    not prove a unique cell of origin.
  phenotype_term:
    preferred_term: Pancreatic adenocarcinoma
    term:
      id: HP:0006725
      label: Pancreatic adenocarcinoma
- category: Clinical
  name: Abdominal Pain
  description: >-
    Abdominal pain is a common presentation; location, neural involvement and disease extent can
    contribute.
  evidence:
  - reference: PMID:25726049
    reference_title: Diagnostic evaluation and staging of pancreatic ductal adenocarcinoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Common signs and symptoms of PDA include abdominal or back pain, jaundice, weight loss, pruritus, and nausea/vomiting.
    explanation: >-
      The diagnostic review supports presentation but provides no numerical frequency denominator.
  - reference: PMID:28785934
    reference_title: Prospective Evaluation of Associations between Cancer-Related Pain and Perineural Invasion in Patients with Resectable Pancreatic Adenocarcinoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Preoperative pain does not predict the presence of perineural invasion or other pathologic prognostic factors in patients with resectable pancreatic adenocarcinoma.
    explanation: >-
      Prospective 52-patient resectable cohort qualifies pain as a neural-invasion surrogate.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
- category: Clinical
  name: Obstructive Jaundice
  description: >-
    Painless obstructive jaundice is a classic presentation for tumors in the
    pancreatic head, caused by compression of the common bile duct.
  phenotype_term:
    preferred_term: Obstructive jaundice
    term:
      id: HP:0001396
      label: Cholestasis
  evidence:
  - reference: PMID:25726049
    reference_title: Diagnostic evaluation and staging of pancreatic ductal adenocarcinoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Common signs and symptoms of PDA include abdominal or back pain, jaundice, weight loss, pruritus, and nausea/vomiting.
    explanation: >-
      The diagnostic review supports presentation but provides no numerical frequency denominator.
- category: Clinical
  name: Weight Loss
  description: >-
    Unintentional weight loss may reflect reduced intake, systemic cancer effects and pancreatic
    exocrine insufficiency; it can precede diagnosis.
  evidence:
  - reference: PMID:25726049
    reference_title: Diagnostic evaluation and staging of pancreatic ductal adenocarcinoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Common signs and symptoms of PDA include abdominal or back pain, jaundice, weight loss, pruritus, and nausea/vomiting.
    explanation: >-
      The diagnostic review supports presentation but provides no numerical frequency denominator.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
- category: Clinical
  name: New-Onset Diabetes
  description: >-
    New or worsening diabetes can precede PDAC diagnosis. Cancer-associated pancreatogenic diabetes
    is distinct from longstanding type 2 diabetes as a risk factor; its mechanisms are incompletely
    resolved.
  evidence:
  - reference: PMID:28507210
    reference_title: Diabetes, Pancreatogenic Diabetes, and Pancreatic Cancer.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The relationships between diabetes and pancreatic ductal adenocarcinoma (PDAC)
      are complex. Longstanding type 2 diabetes (T2DM) is a risk factor for pancreatic
      cancer, but increasing epidemiological data point to PDAC as also a cause of
      diabetes due to unknown mechanisms.
    explanation: >-
      Andersen et al. establish that PDAC causes new-onset diabetes through unknown
      mechanisms, demonstrating the bidirectional relationship between PDAC and diabetes.
  phenotype_term:
    preferred_term: Diabetes mellitus
    term:
      id: HP:0000819
      label: Diabetes mellitus
- category: Clinical
  name: Hepatic Metastases
  description: >-
    Liver is a common metastatic site. The cited registry estimate of 74.36% concerns synchronous
    metastatic cases, not all PDAC or all patients with locally advanced disease.
  evidence:
  - reference: PMID:36776324
    reference_title: A population-based study of synchronous distant metastases and prognosis in patients with PDAC at initial diagnosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was a highest incidence of liver metastases from pancreatic cancer
      (2387,74.36%), followed by lung (625,19.47%), bone (190,5.92%), and brain
      (8,0.25%).
    explanation: >-
      This population-based study of metastatic PDAC directly identifies liver
      metastases as the most common distant metastatic site at diagnosis.
  phenotype_term:
    preferred_term: Hepatic metastasis
    term:
      id: HP:0002896
      label: Neoplasm of the liver
- category: Constitutional
  name: Fatigue
  description: >-
    Fatigue may accompany advanced cancer, nutritional impairment or treatment; it is nonspecific
    and no PDAC-wide frequency is assigned.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- category: Musculoskeletal
  name: Back pain
  description: >-
    Back pain can accompany retroperitoneal and neural involvement but is not specific for PDAC.
  phenotype_term:
    preferred_term: Back pain
    term:
      id: HP:0003418
      label: Back pain
  evidence:
  - reference: PMID:25726049
    reference_title: Diagnostic evaluation and staging of pancreatic ductal adenocarcinoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Common signs and symptoms of PDA include abdominal or back pain, jaundice, weight loss, pruritus, and nausea/vomiting.
    explanation: >-
      The diagnostic review supports presentation but provides no numerical frequency denominator.
- name: Exocrine Pancreatic Insufficiency
  category: Gastrointestinal
  description: >-
    Reduced pancreatic digestive enzyme delivery contributes to maldigestion, malnutrition and weight
    loss, particularly with advanced or pancreatic-head disease.
  phenotype_term:
    preferred_term: Exocrine pancreatic insufficiency
    term:
      id: HP:0001738
      label: Exocrine pancreatic insufficiency
  evidence:
  - reference: PMID:32631175
    reference_title: 'Pancreatic exocrine insufficiency and pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer: A systematic review and meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The pooled prevalence of pancreatic exocrine insufficiency in advanced pancreatic cancer was 72% (95% confidence interval: 55-86%)'
    explanation: >-
      Meta-analysis supports substantial exocrine insufficiency specifically in advanced pancreatic
      cancer; heterogeneity and tumor location limit generalization to all PDAC.
biochemical:
- name: CA 19-9
  evidence:
  - reference: PMID:23331006
    reference_title: 'The clinical utility of CA 19-9 in pancreatic adenocarcinoma: diagnostic and prognostic updates.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 57 studies involving 3,285 pancreatic carcinoma cases, the combined
      sensitivity of CA 19-9 was 78.2% and in 37 studies involving 1,882 cases with
      benign pancreatic disease the specificity of CA 19-9 was 82.8%.
    explanation: >-
      Poruk et al. meta-analysis established CA 19-9 sensitivity of 78.2% and
      specificity of 82.8% for pancreatic carcinoma diagnosis.
  notes: >-
    CA 19-9 assists disease-burden and response assessment; the cited diagnostic sensitivity and
    specificity come from pooled clinical studies, not population screening. It cannot independently
    establish or exclude PDAC.
- name: Carcinoembryonic Antigen (CEA)
  evidence:
  - reference: PMID:23331006
    reference_title: 'The clinical utility of CA 19-9 in pancreatic adenocarcinoma: diagnostic and prognostic updates.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      From the combined analysis of studies reporting CEA, the sensitivity was
      44.2% (1,324 cases) and the specificity was 84.8% (656 cases).
    explanation: >-
      Poruk et al. meta-analysis showed CEA has lower sensitivity (44.2%) than
      CA 19-9 but comparable specificity (84.8%) for pancreatic carcinoma.
  notes: >-
    CEA is a supplementary marker with lower pooled sensitivity than CA 19-9 and similar specificity
    in the cited analysis. Neither is adequate as a stand-alone screening or diagnostic test.
genetic:
- name: KRAS
  gene_term:
    preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  association: Somatic Gain-of-Function Mutation
  inheritance:
  - name: Somatic
  evidence:
  - reference: PMID:33347393
    reference_title: 'Clinical Effect of Driver Mutations of KRAS, CDKN2A/P16, TP53, and SMAD4 in Pancreatic Cancer: A Meta-Analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This systematic review and meta-analysis supports the use of driver mutations in the P53, SMAD4, and KRAS genes as prognostic markers for pancreatic cancer.
    explanation: Directly supports KRAS as an established driver mutation and prognostic marker in pancreatic cancer.
  - reference: DOI:10.3389/fmed.2024.1369136
    reference_title: 'Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In the case of pancreatic ductal adenocarcinomas (PDAC), 90–92% harbor mutations in the oncogene KRAS, triggering canonical MAPK signaling.
    explanation: >-
      Review-level estimate and signaling background; precise frequencies vary by assay and cohort.
  notes: >-
    Activating KRAS mutations occur in most PDAC and many PanIN precursors; G12D, G12V and G12R are
    common alleles. Frequencies depend on cohort and assay. KRAS-wild-type PDAC requires investigation
    for alternative drivers.
- name: TP53
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  association: Somatic Loss-of-Function Mutation
  inheritance:
  - name: Somatic
  evidence:
  - reference: PMID:37404765
    reference_title: Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the KRAS mutated group had a significantly higher percentage of TP53
      (mutated vs wild-type: 80.2% vs 47.6%, p <0.0001)
    explanation: >-
      Foundation Medicine genomic profiling of 9,444 advanced PDAC cases showed TP53
      mutations in 80.2% of KRAS-mutated PDAC.
  notes: >-
    Somatic TP53 disruption cooperates with oncogenic signaling and impairs damage responses. The
    cited advanced-disease profiling cohort reported 80.2% in KRAS-mutated versus 47.6% in KRAS-wild-type
    tumors; these are cohort-specific alteration rates.
- name: SMAD4
  gene_term:
    preferred_term: SMAD4
    term:
      id: hgnc:6770
      label: SMAD4
  association: Somatic Loss-of-Function Mutation
  inheritance:
  - name: Somatic
  evidence:
  - reference: PMID:37404765
    reference_title: Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SMAD4 (mutated vs wild-type: 26.8% vs 15.7%, p <0.0001)
    explanation: >-
      The clinical profiling cohort reports SMAD4 alteration rates by KRAS stratum; it does not explain
      differences between assays.
  notes: >-
    SMAD4 disruption affects TGF-beta signaling. Mutation, deletion and protein-loss assays measure
    different quantities; the cited profiling percentages are not interchangeable with all-mechanism
    inactivation rates.
- name: CDKN2A
  gene_term:
    preferred_term: CDKN2A
    term:
      id: hgnc:1787
      label: CDKN2A
  association: Somatic Loss-of-Function Mutation
  inheritance:
  - name: Somatic
  evidence:
  - reference: PMID:18772397
    reference_title: Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This list includes the classic tumor suppressor genes CDKN2A (p16), SMAD4, and TP53, as well as genes that had not previously been implicated in pancreatic cancer development.
    explanation: Directly identifies CDKN2A/p16 as a classic tumor suppressor gene affected by homozygous deletion in pancreatic cancers.
  - reference: PMID:37404765
    reference_title: Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CDKN2A (mutated vs wild-type: 56.2% vs 34.4%, p <0.0001)
    explanation: >-
      Clinical profiling reports different CDKN2A alteration rates between KRAS strata; it does not
      quantify promoter silencing.
  notes: >-
    Somatic p16-pathway loss can arise through mutation, deletion or silencing and removes CDK4/6
    restraint. These mechanisms should not be assigned a combined frequency from a mutation-only
    assay.
- name: BRCA2
  gene_term:
    preferred_term: BRCA2
    term:
      id: hgnc:1101
      label: BRCA2
  association: Inherited predisposition and somatic homologous-recombination deficiency
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:31157963
    reference_title: Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of
      those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose)
      polymerase (PARP) inhibitor olaparib has had antitumor activity in this population.
    explanation: >-
      The POLO trial confirmed that BRCA-mutated PDAC patients represent a distinct
      subgroup that responds to PARP inhibition, validating the clinical relevance
      of BRCA2 mutations in PDAC.
  notes: >-
    Germline pathogenic variants confer inherited cancer susceptibility; tumor biallelic loss can
    cause homologous-recombination deficiency. Somatic alterations also occur. POLO evidence specifically
    concerns germline BRCA1/2 metastatic cases without progression on platinum.
- name: BRCA1
  gene_term:
    preferred_term: BRCA1
    term:
      id: hgnc:1100
      label: BRCA1
  association: Inherited susceptibility
  inheritance:
  - name: Autosomal dominant
  notes: >-
    Pathogenic germline variants associate with pancreatic cancer risk. Effect estimates derive from
    a predominantly non-Hispanic White registry cohort and require replication across populations;
    this is not an obligatory cause of PDAC.
  evidence:
  - reference: PMID:29922827
    reference_title: Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: BRCA1 (0.6% of cases and 0.2% of controls; OR, 2.58; 95% CI, 1.54-4.05)
    explanation: >-
      Case-control germline association in 3,030 pancreatic cancer cases supports inherited risk,
      not somatic prevalence.
- name: ATM
  gene_term:
    preferred_term: ATM
    term:
      id: hgnc:795
      label: ATM
  association: Inherited susceptibility
  inheritance:
  - name: Autosomal dominant
  notes: >-
    Pathogenic germline variants associate with pancreatic cancer risk. Effect estimates derive from
    a predominantly non-Hispanic White registry cohort and require replication across populations;
    this is not an obligatory cause of PDAC.
  evidence:
  - reference: PMID:29922827
    reference_title: Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ATM (2.3% of cases and 0.37% of controls; OR, 5.71; 95% CI, 4.38-7.33)
    explanation: >-
      Case-control germline association in 3,030 pancreatic cancer cases supports inherited risk,
      not somatic prevalence.
- name: MLH1
  gene_term:
    preferred_term: MLH1
    term:
      id: hgnc:7127
      label: MLH1
  association: Inherited susceptibility
  inheritance:
  - name: Autosomal dominant
  notes: >-
    Pathogenic germline variants associate with pancreatic cancer risk. Effect estimates derive from
    a predominantly non-Hispanic White registry cohort and require replication across populations;
    this is not an obligatory cause of PDAC.
  evidence:
  - reference: PMID:29922827
    reference_title: Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MLH1 (0.13% of cases and 0.02% of controls; OR, 6.66; 95% CI, 1.94-17.53)
    explanation: >-
      Case-control germline association in 3,030 pancreatic cancer cases supports inherited risk,
      not somatic prevalence.
- name: NRG1 Fusions
  gene_term:
    preferred_term: NRG1
    term:
      id: hgnc:7997
      label: NRG1
  association: Somatic oncogenic fusion
  inheritance:
  - name: Somatic
  notes: >-
    NRG1-fusion-positive pancreatic cancer is a molecularly selected subset suitable for HER2/HER3-directed
    therapeutic consideration; it is distinct from acquired RTK feedback after RAS treatment.
  evidence:
  - reference: PMID:39908431
    reference_title: Efficacy of Zenocutuzumab in NRG1 Fusion-Positive Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neuregulin 1 (NRG1) fusions are recurrent oncogenic drivers found in multiple solid tumors.
    explanation: >-
      Primary clinical report describes the fusion-defined molecular treatment subset.
environmental:
- name: Tobacco Smoking
  exposure_term:
    preferred_term: exposure to tobacco smoking
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
  description: >-
    Tobacco use is an established modifiable pancreatic-cancer risk factor. The cited aggregate pancreatic-disease
    risk ratio is not a PDAC-specific estimate and does not establish a causal route through KRAS
    mutation.
  evidence:
  - reference: PMID:34002083
    reference_title: 'Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: there are key modifiable risk factors for pancreatic cancer such as cigarette smoking, obesity, diabetes and alcohol intake.
    explanation: Directly identifies cigarette smoking as a leading modifiable risk factor for pancreatic cancer.
  - reference: PMID:24509242
    reference_title: 'Factors that affect risk for pancreatic disease in the general population: a systematic review and meta-analysis of prospective cohort studies.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Current tobacco use was the single most important risk factor for pancreatic
      diseases (RR, 1.87; 95% CI, 1.54-2.27)
    explanation: >-
      Meta-analysis of 51 population-based prospective cohort studies
      identified tobacco use as the single most important modifiable risk
      factor for pancreatic diseases with an RR of 1.87. The outcome measured
      is pancreatic diseases as a class, and the same abstract reports that
      tobacco has a bigger effect on acute and chronic pancreatitis than on
      pancreatic cancer, so this figure is not a cancer-specific estimate.
- name: Obesity
  description: >-
    Obesity associates with pancreatic disease and is addressed in pancreatic-cancer prevention guidance.
    The cited pooled pancreatic-disease estimate is not specific to PDAC and does not isolate diet
    or a molecular route.
  evidence:
  - reference: PMID:24509242
    reference_title: 'Factors that affect risk for pancreatic disease in the general population: a systematic review and meta-analysis of prospective cohort studies.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      followed by obesity (RR, 1.48; 95% CI, 1.15-1.92)
    explanation: >-
      Meta-analysis of prospective cohort studies identified obesity as the
      second most important risk factor for pancreatic diseases with an RR of 1.48.
treatments:
- name: Surgical Resection
  description: >-
    Resection offers potential long-term disease control in appropriately selected localized PDAC.
    Pancreaticoduodenectomy treats head lesions; distal pancreatectomy treats body/tail lesions.
    Multidisciplinary staging and perioperative or postoperative systemic therapy determine management.
  evidence:
  - reference: PMID:28129987
    reference_title: 'Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eligible patients were aged 18 years or older and had undergone complete
      macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1
      resection).
    explanation: >-
      The ESPAC-4 trial enrolled patients who underwent complete macroscopic resection
      for PDAC, confirming surgical resection as a standard treatment approach with
      adjuvant chemotherapy improving outcomes.
  treatment_term:
    preferred_term: Pancreatectomy
    term:
      id: NCIT:C15294
      label: Pancreatectomy
- name: FOLFIRINOX Chemotherapy
  description: >-
    Combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin. Used as
    first-line treatment for metastatic PDAC in fit patients and as adjuvant therapy
    after surgical resection. Provides superior survival compared to gemcitabine
    alone but with greater toxicity.
  evidence:
  - reference: PMID:30575490
    reference_title: FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer
      survival than gemcitabine among patients with resected pancreatic cancer, at the
      expense of a higher incidence of toxic effects.
    explanation: >-
      The PRODIGE 24 trial demonstrated that adjuvant modified FOLFIRINOX significantly
      improved disease-free and overall survival compared to gemcitabine in resected
      PDAC patients.
  - reference: PMID:21561347
    reference_title: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group
    explanation: >-
      Randomized metastatic trial in patients with ECOG performance status 0 or 1 supports first-line
      use in fit patients, separately from the adjuvant trial.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
    therapeutic_agent:
    - preferred_term: fluorouracil
      term:
        id: CHEBI:46345
        label: 5-fluorouracil
    - preferred_term: leucovorin
      term:
        id: NCIT:C71631
        label: Leucovorin
    - preferred_term: irinotecan
      term:
        id: CHEBI:80630
        label: irinotecan
    - preferred_term: oxaliplatin
      term:
        id: CHEBI:31941
        label: oxaliplatin
  regimen_term:
    preferred_term: modified FOLFIRINOX regimen
    term:
      id: NCIT:C11764
      label: Folfirinox Regimen
- name: Gemcitabine-Based Chemotherapy
  description: >-
    Gemcitabine with nab-paclitaxel improves survival over gemcitabine alone in metastatic PDAC,
    with increased neuropathy and myelosuppression. Regimen selection depends on fitness and prior
    therapy; separate trials do not establish superior tolerability to FOLFIRINOX.
  evidence:
  - reference: PMID:24131140
    reference_title: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      nab-paclitaxel plus gemcitabine significantly improved overall survival,
      progression-free survival, and response rate, but rates of peripheral neuropathy
      and myelosuppression were increased.
    explanation: >-
      The Von Hoff et al. phase 3 trial demonstrated that nab-paclitaxel plus
      gemcitabine significantly improved overall survival (8.5 vs 6.7 months) in
      metastatic pancreatic adenocarcinoma.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
    therapeutic_agent:
    - preferred_term: gemcitabine
      term:
        id: CHEBI:175901
        label: gemcitabine
    - preferred_term: nab-paclitaxel
      term:
        id: NCIT:C2688
        label: Nab-paclitaxel
- name: PARP Inhibitor Therapy
  description: >-
    Maintenance olaparib improves progression-free survival in metastatic PDAC with germline BRCA1/2
    pathogenic variants and no progression after at least 16 weeks of first-line platinum chemotherapy.
    POLO did not show a statistically significant overall-survival benefit in the final analysis.
    This evidence does not extend automatically to every DNA-repair alteration.
  evidence:
  - reference: DOI:10.1200/jco.21.01604
    reference_title: 'Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The phase III POLO study demonstrated significant progression-free survival (PFS) benefit for active olaparib maintenance therapy versus placebo for patients with metastatic pancreatic adenocarcinoma and a germline BRCA mutation.
    explanation: The phase III POLO trial supports maintenance olaparib in germline BRCA-mutated metastatic pancreatic adenocarcinoma; folded in from the former Metastatic_Pancreatic_Adenocarcinoma entry.
  - reference: PMID:31157963
    reference_title: Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to
      evaluate the efficacy of olaparib as maintenance therapy in patients who had a
      germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease
      that had not progressed during first-line platinum-based chemotherapy.
    explanation: >-
      The POLO trial demonstrated that maintenance olaparib significantly prolonged
      progression-free survival in germline BRCA-mutated metastatic pancreatic cancer
      patients who had not progressed on platinum-based chemotherapy.
  - reference: DOI:10.1200/jco.21.01604
    reference_title: 'Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: No statistically significant OS benefit was observed (median 19.0 v 19.2 months; hazard ratio [HR], 0.83; 95% CI, 0.56 to 1.22; P = .3487).
    explanation: >-
      Final POLO analysis qualifies the PFS benefit with the nonsignificant OS comparison.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
- name: Daraxonrasib (RAS(ON) Multiselective Inhibitor)
  description: >-
    Daraxonrasib is a cyclophilin-A-dependent inhibitor of active GTP-bound mutant and wild-type
    RAS. In phase III RASolute 302 for previously treated metastatic PDAC, median overall survival
    was 13.2 versus 6.6 months in the RAS G12 population (hazard ratio 0.40); median progression-free
    survival was 7.3 versus 3.5 months. These clinical outcomes establish treatment efficacy, not
    a universal resistance mechanism or an immune basis for survival benefit.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: daraxonrasib
      term:
        id: CHEBI:746946
        label: daraxonrasib
  target_mechanisms:
  - target: KRAS Oncogene Activation
    treatment_effect: INHIBITS
    description: >-
      Daraxonrasib directly inhibits the active RAS(ON) state produced by
      oncogenic KRAS codon-12 mutations, the initiating driver of PDAC,
      suppressing constitutive RAS-MAPK signaling.
    evidence:
    - reference: PMID:42223072
      reference_title: Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of
        the active guanosine triphosphate-bound state of mutant and wild-type RAS.
      explanation: >-
        The RASolute 302 report describes daraxonrasib's mechanism as direct
        inhibition of the active GTP-bound RAS state driven by mutant KRAS in PDAC.
  - target: Immunosuppressive TME Reversibility under RAS(ON) Inhibition
    treatment_effect: ACTIVATES
    description: >-
      Preclinical PDAC immune remodeling follows RAS inhibition; this is not an inferred immune mechanism
      for the phase III survival effect.
    evidence:
    - reference: PMID:40057911
      reference_title: T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: In this study, we report that RAS(ON) multi-selective inhibition led to rapid and profound PDAC regressions in immunocompetent mice, decreasing myeloid cells and increasing T cells and macrophages in the tumor microenvironment.
      explanation: >-
        Direct PDAC evidence was omitted from the immune report despite being cited in the resistance
        report.
  - target: Regulatory T-Cell Recruitment after KRAS Inhibition
    treatment_effect: ACTIVATES
    description: >-
      Treg recruitment is a model-dependent adaptation documented with daraxonrasib and MRTX1133.
    evidence:
    - reference: DOI:10.1038/s41467-026-75960-3
      reference_title: Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Here, we demonstrate that Kras* targeting using MRTX1133 or Daraxonrasib recruits diverse T-cell infiltrates, including regulatory (Tregs), effector and exhausted T cells into the PDAC microenvironment.
      explanation: >-
        Newer mouse PDAC evidence replaces the unsupported positive Treg-relief node.
  evidence:
  - reference: clinicaltrials:NCT06625320
    reference_title: "RASolute 302: A Phase 3 Multicenter, Open-label, Randomized Study of Daraxonrasib (RMC-6236) Versus Investigator's Choice of Standard of Care Therapy in Patients With Previously Treated Metastatic Pancreatic Ductal Adenocarcinoma (PDAC)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The purpose of this study is to evaluate the safety and efficacy of a novel RAS(ON) inhibitor compared to standard(s) of care (SOC) treatment.
    explanation: ClinicalTrials.gov documents RASolute 302 as a phase 3 evaluation of the RAS(ON) inhibitor daraxonrasib versus standard-of-care chemotherapy in previously treated metastatic PDAC.
  - reference: PMID:42223072
    reference_title: Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of the active guanosine triphosphate-bound state of mutant and wild-type RAS.
    explanation: Establishes daraxonrasib's mechanism of action as a RAS(ON) multiselective tri-complex inhibitor of the active GTP-bound state of mutant and wild-type RAS, the basis for its target_mechanisms link to KRAS-centered signaling.
  - reference: PMID:42223072
    reference_title: Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The median overall survival in the RAS G12 population was 13.2 months with daraxonrasib and 6.6 months with chemotherapy, and the median overall survival in the overall population was 13.2 months and 6.7 months, respectively; the hazard ratio was 0.40 in both populations (P<0.001).
    explanation: RASolute 302 demonstrated a significant overall survival benefit for daraxonrasib over chemotherapy (hazard ratio for death 0.40) in previously treated metastatic PDAC.
  notes: >-
    US regulatory status verified 4 September 2026: FDA approved daraxonrasib (Rasonque) on 26 August
    2026 for adults with metastatic pancreatic adenocarcinoma who have received at least one prior
    systemic therapy or are not candidates for multiagent systemic therapy. This indication is separate
    from the unvalidated checkpoint combinations. Source: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daraxonrasib-metastatic-pancreatic-adenocarcinoma
- name: Experimental Mutant KRAS Vaccine for Residual Disease
  description: >-
    The phase I AMPLIFY-201 trial evaluated ELI-002 2P, an amphiphile G12D/G12R KRAS peptide vaccine
    plus CpG adjuvant, in patients with molecular residual KRAS-mutated pancreatic or colorectal
    cancer. It induced KRAS-specific T-cell responses. This early mixed-cancer study does not establish
    prevention in healthy high-risk individuals or randomized recurrence/survival benefit.
  therapeutic_modality: VACCINE
  treatment_term:
    preferred_term: vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
  evidence:
  - reference: PMID:38195752
    reference_title: 'Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cancer vaccine ELI-002 2P enhances lymph node delivery and immune response using amphiphile (Amph) modification of G12D and G12R mutant KRAS (mKRAS) peptides (Amph-Peptides-2P) together with CpG oligonucleotide adjuvant (Amph-CpG-7909).
    explanation: >-
      Describes the mutant-KRAS amphiphile vaccine platform evaluated in the phase 1
      AMPLIFY-201 trial.
- name: Experimental KRAS Inhibition with Immune Checkpoint Blockade
  description: >-
    Checkpoint combinations with RAS inhibitors are supported by mouse PDAC experiments. RMC-7977/daraxonrasib
    plus PD-1-based therapy worked in one study, whereas a later study found CTLA-4 blockade specifically
    effective and associated with Treg reprogramming and tertiary lymphoid structures. Regimen, model,
    timing and checkpoint partner matter. These results do not establish routine clinical daraxonrasib-checkpoint
    treatment.
  treatment_term:
    preferred_term: Immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
  target_mechanisms:
  - target: Immunosuppressive TME Reversibility under RAS(ON) Inhibition
    treatment_effect: ACTIVATES
    description: >-
      Experimental combinations deepen immune-dependent tumor control.
    evidence:
    - reference: PMID:40057911
      reference_title: T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: the combination of RAS(ON) multi-selective inhibitors with immunotherapy conferred deeper and more durable tumor regressions, including complete responses not seen with either treatment alone.
      explanation: >-
        Direct immunocompetent PDAC combination evidence.
  evidence:
  - reference: DOI:10.1038/s41467-026-75960-3
    reference_title: Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Kras* inhibition induces T-cell influx and offers a therapeutic window to specifically prime PDAC to anti-CTLA4 immune checkpoint blockade efficacy, in contrast to anti-PD1, anti-Tim3, anti-Lag3, anti-Vista, and anti-4-1BB agonist combination therapy.
    explanation: >-
      The newer model-specific comparison qualifies general checkpoint synergy.
- name: NALIRIFOX
  description: >-
    Liposomal irinotecan, oxaliplatin, fluorouracil and leucovorin is a first-line option for fit
    patients with metastatic PDAC. NAPOLI 3 improved median overall survival to 11.1 versus 9.2 months
    compared with gemcitabine-nab-paclitaxel; high-grade toxicity was frequent in both groups.
  treatment_term:
    preferred_term: Chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
    therapeutic_agent:
    - preferred_term: liposomal irinotecan
      term:
        id: NCIT:C82676
        label: Irinotecan Sucrosofate
      description: >-
        The NCIT formulation term describes irinotecan encapsulated in liposomes; this is the
        liposomal irinotecan component of NALIRIFOX.
    - preferred_term: 5-fluorouracil
      term:
        id: CHEBI:46345
        label: 5-fluorouracil
    - preferred_term: leucovorin
      term:
        id: CHEBI:748997
        label: leucovorin
    - preferred_term: oxaliplatin
      term:
        id: CHEBI:31941
        label: oxaliplatin
  delivery_system:
    delivery_platform: LIPOSOME
    description: >-
      Only the irinotecan component is carried in a liposome; the oxaliplatin,
      fluorouracil and leucovorin in this regimen are conventional formulations. The
      carrier is what separates NALIRIFOX from FOLFIRINOX, which delivers free
      irinotecan, so it is part of the regimen's identity rather than a formulation
      footnote. No targeting ligand: a PEGylated liposome accumulates passively.
    evidence:
    - reference: PMID:37708904
      reference_title: 'NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial.'
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: OTHER
      snippet: Liposomal irinotecan (ONIVYDE, ONIVYDE pegylated liposomal; historical names include nal-IRI, MM 398, or PEP02; Ipsen, Cambridge, MA, USA) is a liposomal formulation that encapsulates irinotecan in a lipid bilayer vesicle.
      explanation: >-
        States the carrier directly - irinotecan encapsulated in a lipid bilayer vesicle
        - which is the claim LIPOSOME records. quote_role BACKGROUND records that this is
        the trial report's description of the drug product rather than a result of the
        trial, and evidence_source is OTHER because a product description reports no
        study; grading it HUMAN_CLINICAL would credit the randomized trial with
        establishing the formulation.
  evidence:
  - reference: PMID:37708904
    reference_title: 'NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Median overall survival was 11·1 months (95% CI 10·0-12·1) with NALIRIFOX versus 9·2 months (8·3-10·6) with nab-paclitaxel-gemcitabine
    explanation: >-
      Randomized phase III evidence supports this contemporary chemotherapy option.
  therapeutic_modality: SMALL_MOLECULE
- name: Zenocutuzumab for NRG1 Fusion-Positive Disease
  description: >-
    The HER2/HER3 bispecific antibody targets the NRG1-fusion signaling subset. In the phase II eNRGy
    trial, 15 of 36 evaluable pancreatic-cancer patients responded (42%); this single-arm molecularly
    selected result does not describe unselected PDAC.
  treatment_term:
    preferred_term: Targeted Therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: zenocutuzumab
      term:
        id: CHEBI:757449
        label: zenocutuzumab
  evidence:
  - reference: PMID:39908431
    reference_title: Efficacy of Zenocutuzumab in NRG1 Fusion-Positive Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 15 of 36 patients (42%; 95% CI, 25 to 59) with pancreatic cancer
    explanation: >-
      Pancreatic-cancer subgroup response in the NRG1-fusion-selected eNRGy trial.
  therapeutic_modality: MONOCLONAL_ANTIBODY
- name: Checkpoint Inhibition for MSI-High or Mismatch-Repair-Deficient Disease
  description: >-
    Mismatch-repair deficiency or high microsatellite instability identifies a small
    immune-treatment-sensitive subset. Responses in selected case series should not be generalized
    to microsatellite-stable PDAC or used as a population-wide response estimate. Pembrolizumab
    was used in eight of the nine immunotherapy-treated patients in the cited series; one received
    ipilimumab plus nivolumab, so the pooled response rate is not a pembrolizumab-only estimate.
  treatment_term:
    preferred_term: Immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: pembrolizumab
      term:
        id: NCIT:C106432
        label: Pembrolizumab
  evidence:
  - reference: DOI:10.1136/jitc-2021-004485
    reference_title: Detection of microsatellite instability-high (MSI-H) by liquid biopsy predicts robust and durable response to immunotherapy in patients with pancreatic cancer
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The overall response rate by Response Evaluation Criteria in Solid Tumors was 77% (7/9).
    explanation: >-
      A retrospective nine-patient MSI-high advanced pancreatic-cancer series supports subset activity;
      the small selected denominator limits precision.
  - reference: DOI:10.1136/jitc-2021-004485
    reference_title: Detection of microsatellite instability-high (MSI-H) by liquid biopsy predicts robust and durable response to immunotherapy in patients with pancreatic cancer
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eight out of nine patients received single-agent pembrolizumab (8/9), while one received
      ipilimumab plus nivolumab.
    explanation: >-
      The agent binding identifies the predominant treatment in this small retrospective series; the
      nine-patient outcome includes one different checkpoint regimen.
  therapeutic_modality: MONOCLONAL_ANTIBODY
- name: Nutritional Support
  description: >-
    Assess weight loss and dietary intake and provide individualized nutritional counseling and
    oral supplementation. Nutritional support complements treatment of exocrine insufficiency; it
    is not itself pancreatic enzyme replacement.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:32631175
    reference_title: "Pancreatic exocrine insufficiency and pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Improving the nutritional status, either with parenteral nutrition or oral supplementation,
      can increase the body weight, skeletal muscle mass, fat mass and quality of life, facilitating
      the administration of chemotherapy without interruption.
    explanation: >-
      The review background supports nutritional supplementation as supportive care. This entry
      concerns dietary counseling and oral support; parenteral nutrition is a separate medical route
      and is not represented by the BEHAVIORAL modality.
  therapeutic_modality: BEHAVIORAL
- name: Pancreatic Enzyme Replacement
  description: >-
    Pancreatic enzyme replacement, including pancrelipase, is used for exocrine insufficiency and
    maldigestion when indicated. Mixed observational/trial pooled survival associations do not
    establish a causal survival benefit; an 88-patient randomized trial of pancrelipase in
    unresectable pancreatic cancer did not improve the primary eight-week BMI endpoint.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
    therapeutic_agent:
    - preferred_term: pancrelipase
      term:
        id: CHEBI:753090
        label: pancrelipase
  evidence:
  - reference: PMID:32631175
    reference_title: 'Pancreatic exocrine insufficiency and pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer: A systematic review and meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The pooled prevalence of pancreatic exocrine insufficiency in advanced pancreatic cancer was 72% (95% confidence interval: 55-86%)'
    explanation: >-
      Meta-analysis supports substantial exocrine insufficiency specifically in advanced pancreatic
      cancer; heterogeneity and tumor location limit generalization to all PDAC.
  - reference: PMID:29851751
    reference_title: A Multicenter Open-Label Randomized Controlled Trial of Pancreatic Enzyme Replacement Therapy in Unresectable Pancreatic Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with unresectable PC receiving chemotherapy were randomly assigned to pancrelipase
      and nonpancrelipase groups.
    explanation: >-
      The randomized trial establishes the specific enzyme preparation used in this
      pancreatic-cancer population.
  - reference: PMID:29851751
    reference_title: A Multicenter Open-Label Randomized Controlled Trial of Pancreatic Enzyme Replacement Therapy in Unresectable Pancreatic Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this randomized controlled trial, pancrelipase failed to improve the change in BMI at 8
      weeks in PC patients receiving chemotherapy.
    explanation: >-
      The null primary endpoint prevents presenting enzyme replacement as a proven general
      weight-gain or survival treatment; clinical use for exocrine insufficiency is a separate
      indication.
  therapeutic_modality: PROTEIN_REPLACEMENT
  target_mechanisms:
  - target: Exocrine Pancreatic Insufficiency
    treatment_effect: BYPASSES
    description: >-
      Oral enzyme replacement supplies digestive enzymes to compensate for inadequate endogenous
      pancreatic enzyme delivery; it does not restore destroyed pancreatic tissue.
    evidence:
    - reference: PMID:32631175
      reference_title: "Pancreatic exocrine insufficiency and pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer: A systematic review and meta-analysis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Pancreatic enzyme replacement therapy (PERT) is the standard treatment for PEI.
      explanation: >-
        The review describes symptomatic enzyme replacement for exocrine insufficiency, independently
        of uncertain survival benefit.
- name: Biliary Drainage
  description: >-
    Endoscopic placement of a fully covered self-expandable metallic biliary stent can relieve
    malignant biliary obstruction. Select procedural drainage according to anatomy, symptoms and
    the clinical treatment plan.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:41067164
    reference_title: Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with pancreatic cancer.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In the event of biliary obstruction, endoscopic placement of a fully covered, self-expandable metallic biliary stent is suggested
    explanation: >-
      Guideline addresses biliary obstruction.
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Obstructive Jaundice
    treatment_effect: BYPASSES
    description: >-
      Biliary stenting bypasses the obstructed segment and restores drainage in patients with
      malignant biliary obstruction.
    evidence:
    - reference: PMID:41067164
      reference_title: Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with pancreatic cancer.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: In the event of biliary obstruction, endoscopic placement of a fully covered, self-expandable metallic biliary stent is suggested
      explanation: >-
        Guideline addresses biliary obstruction.
- name: Pain Management
  description: >-
    Provide individualized pain assessment and specialist-guided multimodal analgesia alongside
    cancer-directed therapy. This supportive-care category spans medication and procedural
    approaches, so it does not designate one pharmacologic platform or a single therapeutic agent.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:41067164
    reference_title: Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with pancreatic cancer.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Effective pain control is strongly recommended and should involve a pain control specialist when required
    explanation: >-
      Guideline supports active specialist pain management.
  therapeutic_modality: OTHER
- name: Experimental RAS-EGFR-STAT3 Combination
  description: >-
    Daraxonrasib, afatinib and the STAT3 degrader SD36 produced prolonged regressions in orthotopic,
    genetically engineered and patient-derived xenograft PDAC models. This corrected primary study
    also tested genetic RAF1/EGFR/STAT3 ablation. It supports combination research, not routine patient
    treatment or proof that immunity is irrelevant.
  treatment_term:
    preferred_term: Targeted Therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: daraxonrasib
      term:
        id: CHEBI:746946
        label: daraxonrasib
    - preferred_term: afatinib
      term:
        id: CHEBI:61390
        label: afatinib
    - preferred_term: SD36
      term:
        id: NCIT:C200712
        label: STAT3 Inhibitor
      description: >-
        SD36 is the experimental STAT3-targeting degrader used in the cited study. The binding is to
        the broader STAT3 inhibitor class: OLS searches of CHEBI and NCIT found no specific SD36 or
        SD-36 entity on 5 September 2026.
  target_mechanisms:
  - target: KRAS Oncogene Activation
    treatment_effect: INHIBITS
    description: >-
      Daraxonrasib inhibits active RAS within the experimental daraxonrasib-afatinib-SD36
      combination. Linking the same treatment to RAS signaling and observed resistance prevention
      connects the experimental resistance branch without asserting that initiating KRAS activation
      causes acquired amplification in untreated tumors.
    evidence:
    - reference: PMID:42224594
      reference_title: A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: a combination of selective inhibitors of KRAS (RMC-6236/daraxonrasib), EGFR family (afatinib), and STAT3 (SD36) induced the complete regression of orthotopic PDAC tumors with no evidence of tumor resistance for over 200 d posttreatment.
      explanation: >-
        The corrected mouse-model study identifies daraxonrasib as the KRAS/RAS-directed component of
        the combination. This pharmacologic target link does not establish acquired amplification as a
        consequence of the initiating mutation or identify a human resistance frequency.
  - target: Acquired RAS(ON) Inhibitor Resistance
    treatment_effect: INHIBITS
    description: >-
      Experimental multilevel pathway inhibition delayed or prevented detected resistance within
      the studied follow-up.
    evidence:
    - reference: PMID:42224594
      reference_title: A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: a combination of selective inhibitors of KRAS (RMC-6236/daraxonrasib), EGFR family (afatinib), and STAT3 (SD36) induced the complete regression of orthotopic PDAC tumors with no evidence of tumor resistance for over 200 d posttreatment.
      explanation: >-
        Corrected republication supports pharmacologic mouse-model durability; no human efficacy
        or permanent cure is established.
  evidence:
  - reference: PMID:42224594
    reference_title: A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: a combination of selective inhibitors of KRAS (RMC-6236/daraxonrasib), EGFR family (afatinib), and STAT3 (SD36) induced the complete regression of orthotopic PDAC tumors with no evidence of tumor resistance for over 200 d posttreatment.
    explanation: >-
      Corrected republication supports pharmacologic mouse-model durability; no human efficacy or
      permanent cure is established.
  therapeutic_modality: SMALL_MOLECULE
clinical_trials:
- name: NCT06625320
  description: >-
    RASolute 302: a phase 3, international, open-label, randomized trial comparing
    daraxonrasib (RMC-6236) with the investigator's choice of standard chemotherapy
    in patients with previously treated metastatic PDAC. The trial met its dual
    primary endpoints of overall survival and progression-free survival in the
    RAS G12 population.
  phase: PHASE_III
  target_phenotypes:
  - preferred_term: Neoplasm of the pancreas
    term:
      id: HP:0002894
      label: Neoplasm of the pancreas
  evidence:
  - reference: clinicaltrials:NCT06625320
    reference_title: "RASolute 302: A Phase 3 Multicenter, Open-label, Randomized Study of Daraxonrasib (RMC-6236) Versus Investigator's Choice of Standard of Care Therapy in Patients With Previously Treated Metastatic Pancreatic Ductal Adenocarcinoma (PDAC)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to evaluate the safety and efficacy of a novel
      RAS(ON) inhibitor compared to standard(s) of care (SOC) treatment.
    explanation: >-
      ClinicalTrials.gov confirms RASolute 302 (NCT06625320) evaluated the RAS(ON)
      inhibitor daraxonrasib against standard-of-care chemotherapy in mPDAC.
  - reference: PMID:42223072
    reference_title: Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among patients with previously treated mPDAC, treatment with daraxonrasib led
      to significantly longer overall survival and progression-free survival than
      chemotherapy.
    explanation: >-
      The primary-results publication reports that RASolute 302 met its overall
      survival and progression-free survival endpoints favoring daraxonrasib.
- name: NCT04083235
  description: >-
    NAPOLI 3 randomized first-line NALIRIFOX against gemcitabine-nab-paclitaxel in metastatic pancreatic
    ductal adenocarcinoma.
  phase: PHASE_III
  evidence:
  - reference: PMID:37708904
    reference_title: 'NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Median overall survival was 11·1 months (95% CI 10·0-12·1) with NALIRIFOX versus 9·2 months (8·3-10·6) with nab-paclitaxel-gemcitabine
    explanation: >-
      Published randomized trial provides the outcome; no live recruitment-status claim is inferred.
- name: NCT02184195
  description: >-
    POLO randomized maintenance olaparib versus placebo in germline BRCA1/2 metastatic pancreatic
    cancer without progression on first-line platinum; PFS improved but final OS was not statistically
    different.
  phase: PHASE_III
  evidence:
  - reference: DOI:10.1200/jco.21.01604
    reference_title: 'Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The phase III POLO study demonstrated significant progression-free survival (PFS) benefit for active olaparib maintenance therapy versus placebo for patients with metastatic pancreatic adenocarcinoma and a germline BRCA mutation.
    explanation: The phase III POLO trial supports maintenance olaparib in germline BRCA-mutated metastatic pancreatic adenocarcinoma; folded in from the former Metastatic_Pancreatic_Adenocarcinoma entry.
  - reference: PMID:31157963
    reference_title: Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to
      evaluate the efficacy of olaparib as maintenance therapy in patients who had a
      germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease
      that had not progressed during first-line platinum-based chemotherapy.
    explanation: >-
      The POLO trial demonstrated that maintenance olaparib significantly prolonged
      progression-free survival in germline BRCA-mutated metastatic pancreatic cancer
      patients who had not progressed on platinum-based chemotherapy.
  - reference: DOI:10.1200/jco.21.01604
    reference_title: 'Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: No statistically significant OS benefit was observed (median 19.0 v 19.2 months; hazard ratio [HR], 0.83; 95% CI, 0.56 to 1.22; P = .3487).
    explanation: >-
      Final POLO analysis qualifies the PFS benefit with the nonsignificant OS comparison.
- name: NCT02715804
  description: >-
    HALO 109-301 compared PEGPH20 plus gemcitabine-nab-paclitaxel with placebo plus chemotherapy
    in hyaluronan-high metastatic PDAC. Increased response rate did not improve survival, limiting
    clinical translation of stromal hyaluronan depletion.
  phase: PHASE_III
  evidence:
  - reference: PMID:32706635
    reference_title: Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The addition of PEGPH20 to AG increased the ORR but did not improve OS or PFS.
    explanation: >-
      Randomized trial limits extrapolation from preclinical matrix/hypoperfusion rescue to clinical
      survival.
discussions:
- discussion_id: gap_pdac_caf_program_t_cell_exclusion
  prompt: >-
    Which cancer-associated fibroblast programs actively cause T-cell exclusion
    and checkpoint resistance in PDAC, and which stromal programs are
    tumor-restraining or merely correlative with desmoplastic burden?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Desmoplastic Stroma
  - pathophysiology#CAF-Mediated T Cell Exclusion
  - pathophysiology#Immune Evasion
  rationale: >-
    PDAC desmoplasia is not a single therapeutic target: some CAF states may
    exclude effector T cells, whereas others may restrain invasion. A
    patient-derived organ-on-chip experiment can test whether specific CAF
    programs are causal for immune exclusion and whether reprogramming them
    improves T-cell cytotoxicity without removing tumor-restraining stroma.
  proposed_experiments:
  - experiment_id: exp_pdac_patient_ooc_caf_t_cell_exclusion
    name: Patient-derived PDAC organ-on-chip CAF reprogramming and T-cell infiltration assay
    description: >-
      Assemble a patient-derived PDAC organoid organ-on-chip with fibroblasts,
      endothelium, and immune cells; induce or suppress CAF programs including
      interferon-response CAF states; then measure T-cell infiltration,
      cytotoxicity, tumor viability, and stromal remodeling under checkpoint
      blockade.
    experiment_type:
      preferred_term: patient-derived organ-on-chip immunotherapy perturbation experiment
    model_systems:
    - name: Patient-derived PDAC tumor-microenvironment organ-on-chip
      description: >-
        Microfluidic human PDAC model combining patient-derived tumor organoids
        with fibroblasts, endothelial cells, and immune cells so stromal
        crosstalk, T-cell migration, and drug response can be measured in a
        standardized ex vivo platform.
      experimental_model_type: ORGAN_ON_CHIP
      namo_type: namo:OrganOnChip
      organism:
        preferred_term: human
        term:
          id: NCBITaxon:9606
          label: Homo sapiens
      tissue_term:
        preferred_term: pancreas
        term:
          id: UBERON:0001264
          label: pancreas
      cell_types:
      - preferred_term: pancreatic ductal cell
        term:
          id: CL:0002079
          label: pancreatic ductal cell
      - preferred_term: fibroblast
        term:
          id: CL:0000057
          label: fibroblast
      - preferred_term: endothelial cell
        term:
          id: CL:0000115
          label: endothelial cell
      - preferred_term: T cell
        term:
          id: CL:0000084
          label: T cell
      cell_source: patient-derived organoids plus matched stromal and immune-cell compartments
      culture_system: perfused microfluidic organ-on-chip with extracellular-matrix scaffold
    perturbations:
    - name: CAF subtype induction and depletion
      target: pathophysiology#Desmoplastic Stroma
      description: >-
        Induce, suppress, or selectively deplete CAF states to separate
        immune-excluding and tumor-restraining stromal programs.
      genes:
      - preferred_term: FAP
      biological_processes:
      - preferred_term: extracellular matrix organization
        term:
          id: GO:0030198
          label: extracellular matrix organization
    - name: STING-driven interferon-response CAF induction
      target: pathophysiology#CAF-Mediated T Cell Exclusion
      description: >-
        STING agonism or matched interferon-response induction used to test
        whether an interferon-response CAF state decreases invasion and improves
        antitumor immune activity.
      biological_processes:
      - preferred_term: type I interferon signaling pathway
        term:
          id: GO:0060337
          label: type I interferon-mediated signaling pathway
    - name: Immune checkpoint blockade
      target: pathophysiology#Immune Evasion
      description: >-
        Anti-PD-1/PD-L1 or matched checkpoint blockade applied with CAF
        perturbation to test whether stromal reprogramming is required for
        T-cell cytotoxicity.
      treatment_term:
        preferred_term: immunotherapy
        term:
          id: NCIT:C15262
          label: Immunotherapy
    readouts:
    - name: T-cell infiltration and cytotoxicity
      target: pathophysiology#CAF-Mediated T Cell Exclusion
      description: >-
        Spatial T-cell entry into tumor organoid regions, activation markers,
        and tumor-cell killing after CAF-state perturbation.
      biological_processes:
      - preferred_term: T cell activation
        term:
          id: GO:0042110
          label: T cell activation
      assays:
      - preferred_term: high-content live imaging
      - preferred_term: cytotoxicity assay
      direction: NEGATIVE
    - name: CAF-state trajectory
      target: pathophysiology#Desmoplastic Stroma
      description: >-
        Single-cell and spatial profiling of inflammatory, myofibroblastic, and
        interferon-response CAF programs after stromal perturbation.
      assays:
      - preferred_term: single-cell transcriptomic profiling
      - preferred_term: spatial transcriptomic profiling
      direction: POSITIVE
    - name: Tumor organoid viability under checkpoint blockade
      target: pathophysiology#Immune Evasion
      description: Tumor-cell survival after combined CAF perturbation and checkpoint blockade.
      assays:
      - preferred_term: cell viability assay
      direction: NEGATIVE
    controls:
    - name: Tumor organoid without CAF compartment
      description: Patient-derived PDAC organoid chip lacking fibroblasts.
    - name: CAF-intact chip without T cells
      description: Stromal chip lacking effector T cells to distinguish direct stromal effects from immune-mediated killing.
    - name: Isotype-control checkpoint antibody
      description: Matched antibody control for checkpoint blockade.
    decision_criterion: >-
      A causal CAF immune-exclusion program is supported if its induction
      reduces T-cell entry or killing and its suppression restores checkpoint
      response. A tumor-restraining CAF state is supported if induction lowers
      invasion or viability while preserving or improving T-cell function.
    would_support:
    - pathophysiology#CAF-Mediated T Cell Exclusion
    - pathophysiology#Immune Evasion
    would_refute:
    - pathophysiology#CAF-Mediated T Cell Exclusion
    evidence:
    - reference: PMID:41610338
      reference_title: A Patient-Derived Organ-on-Chip Platform for Modeling the Tumor Microenvironment and Drug Responses in Pancreatic Cancer.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: incorporating PDOs with key components of the TME (fibroblasts, endothelial cells, and immune cells) within a microfluidic system
      explanation: >-
        Provides the recent patient-derived organ-on-chip precedent for a
        PDAC tumor-microenvironment experiment with stromal and immune
        compartments.
    - reference: PMID:41610338
      reference_title: A Patient-Derived Organ-on-Chip Platform for Modeling the Tumor Microenvironment and Drug Responses in Pancreatic Cancer.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: model and assess the efficacy of immune checkpoint blockade for T cell cytotoxicity in PDAC
      explanation: >-
        Supports using this platform to adjudicate checkpoint response in the
        presence of patient-derived stromal context.
    - reference: PMID:40215177
      reference_title: Dissecting FAP+ Cell Diversity in Pancreatic Cancer Uncovers an Interferon-Response Subtype of Cancer-Associated Fibroblasts with Tumor-Restraining Properties.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: identifies an ifCAF subtype that can be induced to suppress protumorigenic features of PDAC
      explanation: >-
        Motivates testing CAF reprogramming rather than treating all desmoplasia
        as uniformly protumorigenic.
disease_term:
  preferred_term: pancreatic ductal adenocarcinoma
  term:
    id: MONDO:0005184
    label: pancreatic ductal adenocarcinoma
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0005184
      label: pancreatic ductal adenocarcinoma
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: MONDO provides an exact disease term for pancreatic ductal adenocarcinoma.
  ncit_mappings:
  - term:
      id: NCIT:C9120
      label: Pancreatic Ductal Adenocarcinoma
    mapping_predicate: skos:exactMatch
    mapping_source: NCIT
    mapping_justification: NCIT provides an exact neoplasm term for pancreatic ductal adenocarcinoma.
datasets:
- accession: geo:GSE111672
  title: Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas
  description: >-
    Multimodal PDAC dataset combining spatial transcriptomics and single-cell RNA-seq
    from primary pancreatic tumors. Useful for resolving how malignant ductal cells,
    macrophages, dendritic cells, and fibroblast states are spatially organized within
    the tumor microenvironment.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MULTI_OMICS
  sample_types:
  - preferred_term: pancreatic tumor tissue
    tissue_term:
      preferred_term: pancreas
      term:
        id: UBERON:0001264
        label: pancreas
  sample_count: 23
  conditions:
  - primary pancreatic ductal adenocarcinoma
  publication: PMID:31932730
  notes: >-
    GEO has 23 sample records derived from six patients with single-cell and spatial measurements.
    Assay/sample count is not the number of independent patient tumors. Spatial colocalization supports
    ecological hypotheses but not causal cell-cell signaling.
- accession: geo:GSE154778
  title: Single-cell transcriptomics analysis of pancreatic primary tumor and metastatic biopsy tissues
  description: >-
    Single-cell RNA-seq of 10 pancreatic primary tumors and 6 metastatic biopsies.
    Captures tumor, stromal, and immune programs across primary and metastatic disease,
    making it useful for modeling dissemination and metastatic niche adaptation in PDAC.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: pancreatic tumor tissue
    tissue_term:
      preferred_term: pancreas
      term:
        id: UBERON:0001264
        label: pancreas
  sample_count: 16
  conditions:
  - primary pancreatic ductal adenocarcinoma
  - metastatic pancreatic ductal adenocarcinoma
  publication: PMID:32988401
  notes: >-
    GEO reports 10 primary tumors and 6 metastatic lesion biopsies profiled on the
    10x Genomics Chromium platform. High-value bridge dataset between primary-tumor
    ecology and metastatic evolution.
- accession: geo:GSE155698
  title: Multimodal Mapping of the Tumor and Peripheral Blood Immune Landscape in Human Pancreatic Cancer
  description: >-
    Single-cell immune-focused PDAC resource spanning tumor tissue, adjacent normal
    pancreas, and peripheral blood mononuclear cells from pancreatic cancer patients,
    plus healthy-donor PBMC controls. Especially useful for linking the local TME to
    the systemic macroenvironment.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: pancreatic tumor tissue
    tissue_term:
      preferred_term: pancreas
      term:
        id: UBERON:0001264
        label: pancreas
  - preferred_term: adjacent normal pancreatic tissue
    tissue_term:
      preferred_term: pancreas
      term:
        id: UBERON:0001264
        label: pancreas
  - preferred_term: peripheral blood
    tissue_term:
      preferred_term: blood
      term:
        id: UBERON:0000178
        label: blood
  sample_count: 41
  conditions:
  - pancreatic ductal adenocarcinoma tumor tissue
  - adjacent normal pancreas
  - pancreatic cancer patient PBMCs
  - healthy donor PBMCs
  publication: PMID:34296197
  notes: >-
    Live GEO metadata lists 41 sample records, while the submitted design describes 16 tumor, 3 adjacent
    normal, 16 patient PBMC and 4 healthy PBMC samples (39 total). The discrepancy is preserved explicitly;
    reconcile the GSM-level manifest before cohort analysis and do not equate sample records with
    independent patients. Raw data are described as deposited in dbGaP phs002071.v1.p1; this review
    did not access controlled individual data.
- accession: geo:GSE62452
  title: Microarray gene-expression profiles of 69 pancreatic tumors and 61 adjacent non-tumor tissue from patients with pancreatic ductal adenocarcinoma
  description: >-
    Large paired bulk expression cohort of PDAC tumors and adjacent non-tumor tissue.
    Useful as a broader transcriptomic reference set for tumor-versus-normal contrasts
    and for anchoring subtype-level or pathway-level signatures in a larger patient cohort.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_types:
  - preferred_term: pancreatic tumor tissue
    tissue_term:
      preferred_term: pancreas
      term:
        id: UBERON:0001264
        label: pancreas
  sample_count: 130
  conditions:
  - pancreatic ductal adenocarcinoma tumor tissue
  - adjacent non-tumor pancreatic tissue
  publication: PMID:27197190
  notes: >-
    GEO reports 69 pancreatic tumors and 61 adjacent non-tumor tissues, with earlier
    Affymetrix data from GSE28735 incorporated into the merged normalized cohort.
    Useful as a bulk-expression complement to the single-cell and spatial resources above.
computational_models:
- name: PDAC CAF-Mediated Invasion PhysiCell Model
  description: >-
    Grammar-based PhysiCell agent-based model of pancreatic ductal adenocarcinoma neoplastic cells
    and cancer-associated fibroblasts. The model encodes fibroblast-mediated invasion, epithelial-mesenchymal
    state switching, and ECM-dependent motility tradeoffs using human-interpretable cell rules informed
    by PDAC spatial transcriptomics and coculture data.
  model_type: AGENT_BASED
  repository_url: https://github.com/PhysiCell-Models/grammar_samples/tree/v2.0.1/user_projects/epi_caf_invasion
  model_id: grammar_samples:v2.0.1/user_projects/epi_caf_invasion
  base_model: PhysiCell grammar manuscript release DOI:10.5281/zenodo.16285252
  model_software: PhysiCell
  model_format: C++/XML/CSV
  publication: DOI:10.1016/j.cell.2025.06.048
  modeled_mechanisms:
  - target: Desmoplastic Stroma
    description: >-
      Implements ECM-driven fibroblast motility and epithelial-mesenchymal state
      switching encoded in `config/cell_rules.csv` for the stromal invasion program.
  findings:
  - statement: ECM increases epithelial-to-mesenchymal switching of tumor epithelial cells in the executable PDAC invasion model.
    supporting_text: epithelial_tumor,ecm,increases,transform to mesenchymal_tumor,0.01,0.01,4,0
  - statement: Fibroblast migration is explicitly controlled by ECM-dependent rules in the invasion model.
    supporting_text: fibroblast,ecm,increases,migration speed,3.470551875,9.999679617,1.153017946,0
  variables:
  - name: inflammatory_signal
    dataset_identifier: inflammatory_signal
    description: Generic inflammatory signaling field used to bias migration and mesenchymal-to-epithelial state transitions.
    unit: dimensionless field
  - name: ecm
    dataset_identifier: ecm
    description: Extracellular-matrix density field driving stromal invasion and epithelial-mesenchymal plasticity.
    unit: dimensionless field
    mappings_list:
    - preferred_term: Extracellular matrix
      term:
        id: GO:0031012
        label: extracellular matrix
  - name: epithelial_normal_cells
    dataset_identifier: epithelial_normal
    description: Abundance of non-malignant epithelial agents in the coculture invasion simulation.
    unit: cells
    mappings_list:
    - preferred_term: epithelial cell
      term:
        id: CL:0000066
        label: epithelial cell
  - name: mesenchymal_normal_cells
    dataset_identifier: mesenchymal_normal
    description: Abundance of non-malignant mesenchymal-state agents in the invasion simulation.
    unit: cells
    mappings_list:
    - preferred_term: mesenchymal cell
      term:
        id: CL:0008019
        label: mesenchymal cell
  - name: fibroblast_cells
    dataset_identifier: fibroblast
    description: Abundance of fibroblast / CAF-like agents in the invasion simulation.
    unit: cells
    mappings_list:
    - preferred_term: fibroblast
      term:
        id: CL:0000057
        label: fibroblast
  - name: epithelial_tumor_cells
    dataset_identifier: epithelial_tumor
    description: Abundance of epithelial-state malignant agents in the invasion simulation.
    unit: cells
    mappings_list:
    - preferred_term: epithelial tumor cell
      term:
        id: CL:0000066
        label: epithelial cell
  - name: mesenchymal_tumor_cells
    dataset_identifier: mesenchymal_tumor
    description: Abundance of mesenchymal-state malignant agents in the invasion simulation.
    unit: cells
    mappings_list:
    - preferred_term: mesenchymal tumor cell
      term:
        id: CL:0008019
        label: mesenchymal cell
  notes: >-
    Manuscript-synced sample model from the official PhysiCell grammar_samples release. Relevant
    configs include `config/PhysiCell_settings_PDAC.xml`, the rule table in `config/cell_rules.csv`,
    and coculture initial conditions under `config/ics/`. The pinned v2.0.1 repository, XML configurations
    and rule tables were inspected in this review. This is a published computational model record;
    no simulation, calibration or patient-response validation was performed here, and it does not
    establish daraxonrasib immune or resistance predictions.
- name: PDAC Immunotherapy PhysiCell Model
  description: >-
    Grammar-based PhysiCell agent-based PDAC tumor-immune model initialized from PDAC tissue compositions.
    The model simulates combination therapy with GVAX, nivolumab, and urelumab across heterogeneous
    baseline microenvironment states using explicit cell-state and interaction rules.
  model_type: AGENT_BASED
  repository_url: https://github.com/PhysiCell-Models/grammar_samples/tree/v2.0.1/user_projects/pdac_therapy
  model_id: grammar_samples:v2.0.1/user_projects/pdac_therapy
  base_model: PhysiCell grammar manuscript release DOI:10.5281/zenodo.16285252
  model_software: PhysiCell
  model_format: C++/XML/CSV
  publication: DOI:10.1016/j.cell.2025.06.048
  modeled_mechanisms:
  - target: Immune Evasion
    description: >-
      Encodes PD-L1-dependent suppression of T-cell motility and attack probabilities,
      plus macrophage inflammatory-state rules, in `config/cell_rules.csv`.
  findings:
  - statement: Contact with PD-L1-high tumor cells reduces CD8 T-cell migration in the executable PDAC immunotherapy model.
    supporting_text: PD-1lo_CD137lo_CD8_Tcell,contact with PD-L1hi_tumor,decreases,migration speed,0,0.1,2,0
  - statement: Anti-inflammatory signals decrease CD8 T-cell attack against tumor cells in the executable PDAC immunotherapy model.
    supporting_text: PD-1lo_CD137hi_CD8_Tcell,anti-inflammatory factor,decreases,attack PD-L1hi_tumor,0,2.5,2,0
  - statement: Macrophage oxygen sensing controls pro- versus anti-inflammatory factor secretion in the executable PDAC immunotherapy model.
    supporting_text: macrophage,oxygen,decreases,anti-inflammatory factor secretion,0,5,4,0
  variables:
  - name: oxygen
    dataset_identifier: oxygen
    description: Diffusible oxygen field used to control tumor proliferation, macrophage polarization logic, and necrotic stress.
    unit: substrate density
    mappings_list:
    - preferred_term: dioxygen
      term:
        id: CHEBI:15379
        label: dioxygen
  - name: debris
    dataset_identifier: debris
    description: Extracellular dead-cell debris field that attracts macrophages and reflects local cell death burden.
    unit: substrate density
  - name: pro_inflammatory_factor
    dataset_identifier: pro-inflammatory factor
    description: Generic pro-inflammatory signaling field that boosts T-cell attack and chemotaxis in the model.
    unit: substrate density
  - name: anti_inflammatory_factor
    dataset_identifier: anti-inflammatory factor
    description: Generic anti-inflammatory signaling field that suppresses T-cell migration and attack in the model.
    unit: substrate density
  - name: PD-L1lo_tumor_cells
    dataset_identifier: PD-L1lo_tumor
    description: Abundance of PD-L1-low malignant epithelial agents in the PDAC immunotherapy simulation.
    unit: cells
    mappings_list:
    - preferred_term: epithelial tumor cell
      term:
        id: CL:0000066
        label: epithelial cell
  - name: PD-L1hi_tumor_cells
    dataset_identifier: PD-L1hi_tumor
    description: Abundance of PD-L1-high malignant epithelial agents in the PDAC immunotherapy simulation.
    unit: cells
    mappings_list:
    - preferred_term: epithelial tumor cell
      term:
        id: CL:0000066
        label: epithelial cell
    - preferred_term: Programmed cell death 1 ligand 1
      term:
        id: NCIT:C96024
        label: Programmed Cell Death 1 Ligand 1
  - name: macrophages
    dataset_identifier: macrophage
    description: Abundance of macrophage agents in the PDAC immunotherapy simulation.
    unit: cells
    mappings_list:
    - preferred_term: macrophage
      term:
        id: CL:0000235
        label: macrophage
  - name: PD-1hi_CD137lo_CD8_T_cells
    dataset_identifier: PD-1hi_CD137lo_CD8_Tcell
    description: Abundance of PD-1-high CD137-low CD8 T-cell agents in the PDAC immunotherapy simulation.
    unit: cells
    mappings_list:
    - preferred_term: PD-1-high CD137-low CD8 T cell
      term:
        id: CL:0000625
        label: CD8-positive, alpha-beta T cell
  - name: PD-1lo_CD137lo_CD8_T_cells
    dataset_identifier: PD-1lo_CD137lo_CD8_Tcell
    description: Abundance of PD-1-low CD137-low CD8 T-cell agents in the PDAC immunotherapy simulation.
    unit: cells
    mappings_list:
    - preferred_term: PD-1-low CD137-low CD8 T cell
      term:
        id: CL:0000625
        label: CD8-positive, alpha-beta T cell
  - name: PD-1hi_CD137hi_CD8_T_cells
    dataset_identifier: PD-1hi_CD137hi_CD8_Tcell
    description: Abundance of PD-1-high CD137-high CD8 T-cell agents in the PDAC immunotherapy simulation.
    unit: cells
    mappings_list:
    - preferred_term: PD-1-high CD137-high CD8 T cell
      term:
        id: CL:0000625
        label: CD8-positive, alpha-beta T cell
  - name: PD-1lo_CD137hi_CD8_T_cells
    dataset_identifier: PD-1lo_CD137hi_CD8_Tcell
    description: Abundance of PD-1-low CD137-high CD8 T-cell agents in the PDAC immunotherapy simulation.
    unit: cells
    mappings_list:
    - preferred_term: PD-1-low CD137-high CD8 T cell
      term:
        id: CL:0000625
        label: CD8-positive, alpha-beta T cell
  - name: PD-1hi_CD4_T_cells
    dataset_identifier: PD-1hi_CD4_Tcell
    description: Abundance of PD-1-high CD4 T-cell agents in the PDAC immunotherapy simulation.
    unit: cells
    mappings_list:
    - preferred_term: PD-1-high CD4 T cell
      term:
        id: CL:0000624
        label: CD4-positive, alpha-beta T cell
  - name: PD-1lo_CD4_T_cells
    dataset_identifier: PD-1lo_CD4_Tcell
    description: Abundance of PD-1-low CD4 T-cell agents in the PDAC immunotherapy simulation.
    unit: cells
    mappings_list:
    - preferred_term: PD-1-low CD4 T cell
      term:
        id: CL:0000624
        label: CD4-positive, alpha-beta T cell
  notes: >-
    Manuscript-synced sample model from the official PhysiCell grammar_samples release. Therapy-specific
    initial-condition files are stored in `config/ic_cells/`, and the core executable interaction
    logic is in `config/cell_rules.csv`. The pinned v2.0.1 repository, XML configurations and rule
    tables were inspected in this review. This is a published computational model record; no simulation,
    calibration or patient-response validation was performed here, and it does not establish daraxonrasib
    immune or resistance predictions.
references:
- reference: DOI:10.1146/annurev-pathmechdis-031621-024600
  title: Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance
  found_in:
  - Pancreatic_Ductal_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: PDAC has a prominent and spatially heterogeneous stromal microenvironment that meaningfully shapes treatment resistance.
    supporting_text: Pancreatic ductal adenocarcinoma (PDAC) features a prominent stromal microenvironment with remarkable cellular and spatial heterogeneity that meaningfully impacts disease biology and treatment resistance.
- reference: DOI:10.1158/2159-8290.CD-23-0428
  title: Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer
  found_in:
  - Pancreatic_Ductal_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: Functionally distinct fibroblast states are part of the immunosuppressive circuitry of pancreatic cancer.
    supporting_text: Senescence defines a distinct subset of myofibroblasts that orchestrates immunosuppression in pancreatic cancer.
- reference: DOI:10.1001/jamaoncol.2024.1930
  title: Pancreatic Cancer Surveillance and Survival of High-Risk Individuals
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: >-
      Observational surveillance of high-risk individuals associated detection with earlier stage
      and longer survival; selection and lead-time limitations prevent interpreting this as randomized
      population-screening benefit.
- reference: DOI:10.1038/s41467-023-40727-7
  title: Single cell transcriptomic analyses implicate an immunosuppressive tumor microenvironment in pancreatic cancer liver metastasis
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: >-
      Single-cell profiling characterizes immunosuppressive populations in pancreatic-cancer liver
      metastases. Observational cell-state associations do not establish universal resistance to
      all targeted and immune therapies.
- reference: DOI:10.1038/s41591-024-03075-7
  title: Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: >-
      A multiparameter premetastatic-liver study links tissue features with subsequent metastatic
      outcome; predictive associations are not proof of each niche mechanism or a broadly validated
      clinical diagnostic test.
- reference: DOI:10.1136/jitc-2021-004485
  title: Detection of microsatellite instability-high (MSI-H) by liquid biopsy predicts robust and durable response to immunotherapy in patients with pancreatic cancer
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: >-
      Liquid-biopsy-selected MSI-high pancreatic cancer showed immunotherapy activity in a small
      retrospective series; seven responses among nine evaluable patients cannot be generalized to
      unselected PDAC.
- reference: DOI:10.1186/s12943-024-02003-0
  title: Single-cell transcriptome analysis reveals subtype-specific clonal evolution and microenvironmental changes in liver metastasis of pancreatic adenocarcinoma and their clinical implications
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes.
    supporting_text: Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes.
    evidence:
    - reference: DOI:10.1186/s12943-024-02003-0
      reference_title: Single-cell transcriptome analysis reveals subtype-specific clonal evolution and microenvironmental changes in liver metastasis of pancreatic adenocarcinoma and their clinical implications
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes.
      explanation: Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.
- reference: DOI:10.1200/jco.21.01604
  title: 'Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer'
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: >-
      Final POLO follow-up did not show statistically significant overall-survival improvement despite
      the previously demonstrated maintenance progression-free-survival benefit.
- reference: DOI:10.12688/f1000research.21981.1
  title: Recent advances in the treatment of pancreatic cancer
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: >-
      Historical treatment review supplies background; contemporary regimen efficacy is grounded
      in the primary randomized trials elsewhere in the model.
- reference: DOI:10.3322/caac.21820
  title: Cancer statistics, 2024
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: >-
      Population cancer statistics concern calendar-year and disease-site groupings; all-pancreatic-cancer
      survival is not an interchangeable PDAC stage-specific estimate.
- reference: DOI:10.3390/curroncol31090385
  title: Systemic Therapy for Metastatic Pancreatic Cancer—Current Landscape and Future Directions
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: >-
      Review of systemic therapy and molecularly selected treatment strategies; individual trial
      outcomes are verified against the primary publications.
- reference: DOI:10.3390/onco5030037
  title: 'Pancreatic Cancer: Epidemiology, Risk Factors, and Prevention'
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: >-
      Review of epidemiology and risk factors; modifiable-risk associations and proposed screening/prevention
      strategies are distinguished from proven individual molecular causes.
- reference: DOI:10.1038/s41467-026-75960-3
  title: Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer
- reference: DOI:10.1093/carcin/bgae064
  title: 'From precursor to cancer: decoding the intrinsic and extrinsic pathways of pancreatic intraepithelial neoplasia progression'
- reference: DOI:10.1186/s12943-023-01813-y
  title: Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma
- reference: DOI:10.3389/fmed.2024.1369136
  title: 'Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies'
- reference: PMID:17349585
  title: Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice.
- reference: PMID:18772397
  title: Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.
- reference: PMID:21406549
  title: Pancreatic cancers require autophagy for tumor growth.
- reference: PMID:21561347
  title: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.
- reference: PMID:22439937
  title: Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma.
- reference: PMID:22541435
  title: Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.
- reference: PMID:22698407
  title: Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia.
- reference: PMID:23331006
  title: 'The clinical utility of CA 19-9 in pancreatic adenocarcinoma: diagnostic and prognostic updates.'
- reference: PMID:23535601
  title: Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway.
- reference: PMID:23665962
  title: Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells.
- reference: PMID:24131140
  title: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.
- reference: PMID:24277834
  title: Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer.
- reference: PMID:24509242
  title: 'Factors that affect risk for pancreatic disease in the general population: a systematic review and meta-analysis of prospective cohort studies.'
- reference: PMID:24856585
  title: Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma.
- reference: PMID:24856586
  title: Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival.
- reference: PMID:25644265
  title: Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein.
- reference: PMID:25726049
  title: Diagnostic evaluation and staging of pancreatic ductal adenocarcinoma.
- reference: PMID:25985394
  title: Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.
- reference: PMID:26343385
  title: Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma.
- reference: PMID:26560028
  title: Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer.
- reference: PMID:26592447
  title: p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells.
- reference: PMID:28129987
  title: 'Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial.'
- reference: PMID:28507210
  title: Diabetes, Pancreatogenic Diabetes, and Pancreatic Cancer.
- reference: PMID:29922827
  title: Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer.
- reference: PMID:30366930
  title: IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma.
- reference: PMID:30575490
  title: FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer.
- reference: PMID:31157963
  title: Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer.
- reference: PMID:32376951
  title: Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I.
- reference: PMID:32631175
  title: 'Pancreatic exocrine insufficiency and pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer: A systematic review and meta-analysis.'
- reference: PMID:33347393
  title: 'Clinical Effect of Driver Mutations of KRAS, CDKN2A/P16, TP53, and SMAD4 in Pancreatic Cancer: A Meta-Analysis.'
- reference: PMID:34002083
  title: 'Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors.'
- reference: PMID:35142721
  title: 'Chronic Pancreatitis Is a Risk Factor for Pancreatic Cancer, and Incidence Increases With Duration of Disease: A Systematic Review and Meta-analysis.'
- reference: PMID:35176433
  title: Ductal metaplasia in pancreas.
- reference: PMID:35302596
  title: Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma.
- reference: PMID:35449152
  title: HGF/c-Met pathway facilitates the perineural invasion of pancreatic cancer by activating the mTOR/NGF axis.
- reference: PMID:36776324
  title: A population-based study of synchronous distant metastases and prognosis in patients with PDAC at initial diagnosis.
- reference: PMID:36977556
  title: FAK suppresses antigen processing and presentation to promote immune evasion in pancreatic cancer.
- reference: PMID:37404765
  title: Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma.
- reference: PMID:37625401
  title: KRAS(G12D) inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8(+) T cells.
- reference: PMID:37708904
  title: 'NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial.'
- reference: PMID:38195752
  title: 'Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial.'
- reference: PMID:38588697
  title: Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.
- reference: PMID:38727236
  title: Reshaping the Tumor Microenvironment of KRASG12D Pancreatic Ductal Adenocarcinoma with Combined SOS1 and MEK Inhibition for Improved Immunotherapy Response.
- reference: PMID:39908431
  title: Efficacy of Zenocutuzumab in NRG1 Fusion-Positive Cancer.
- reference: PMID:40057911
  title: T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma.
- reference: PMID:40215177
  title: Dissecting FAP+ Cell Diversity in Pancreatic Cancer Uncovers an Interferon-Response Subtype of Cancer-Associated Fibroblasts with Tumor-Restraining Properties.
- reference: PMID:40966362
  title: KRAS Inhibition Activates an Actionable CD24 "Do Not Eat Me" Signal in Pancreatic Cancer.
- reference: PMID:41067164
  title: Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with pancreatic cancer.
- reference: PMID:41545339
  title: Vertical RAS pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations.
- reference: PMID:41572361
  title: CRISPR knockout screens reveal JUN as the master mediator of resistance to MAPK inhibition in KRAS-mutant pancreatic cancer.
- reference: PMID:41610338
  title: A Patient-Derived Organ-on-Chip Platform for Modeling the Tumor Microenvironment and Drug Responses in Pancreatic Cancer.
- reference: PMID:41959066
  title: Targeting Distinct Cell Cycle Nodes Overcomes KRAS/RAS Inhibitor Resistance.
- reference: PMID:42223072
  title: Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer.
- reference: PMID:42224594
  title: A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance.
- reference: PMID:42392864
  title: USP20 promotes CD8(+) T cell exhaustion and impairs KRAS(G12D) inhibitor efficacy by orchestrating cholesterol metabolism and autophagy in pancreatic cancer.
- reference: PMID:42436354
  title: CDK8 remodels the tumor microenvironment and promotes resistance to KRAS(G12D) inhibitors and daraxonrasib in PDAC.
- reference: PMID:42465401
  title: 'Overcoming Daraxonrasib Resistance: Allele-Specific Mechanisms Guide Salvage Therapy in Pancreatic Cancer.'
- reference: PMID:42523238
  title: The basal cell state maintains pancreatic cancers by controlling an immunosuppressive circuit.
- reference: PMID:42581230
  title: Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.
- reference: clinicaltrials:NCT06625320
  title: "RASolute 302: A Phase 3 Multicenter, Open-label, Randomized Study of Daraxonrasib (RMC-6236) Versus Investigator's Choice of Standard of Care Therapy in Patients With Previously Treated Metastatic Pancreatic Ductal Adenocarcinoma (PDAC)"
- reference: PMID:22265420
  title: EMT and dissemination precede pancreatic tumor formation.
- reference: PMID:10561305
  title: Nerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer.
- reference: PMID:28785934
  title: Prospective Evaluation of Associations between Cancer-Related Pain and Perineural Invasion in Patients with Resectable Pancreatic Adenocarcinoma.
- reference: PMID:32706635
  title: Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma.
classifications:
  icdo_morphology:
    classification_value: Adenocarcinoma
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
mechanistic_hypotheses:
- hypothesis_group_id: ras_on_inhibition_immune_tme_remodeling
  hypothesis_label: RAS(ON) Inhibition Remodels the Immunosuppressive Microenvironment
  status: EMERGING
  description: >-
    RAS(ON) multiselective inhibition directly remodels PDAC immunity in mouse models, including
    increased tumor MHC-I, altered myeloid states and T-cell/cDC-dependent responses. Checkpoint
    cotreatment can deepen control, but optimal partners, Treg behavior and durability vary by model.
    Neither universal Treg relief nor clinical daraxonrasib-checkpoint benefit is established. Autophagy
    and FAK are complementary antigen-presentation regulators rather than mutually exclusive alternatives.
  evidence:
  - reference: PMID:40057911
    reference_title: T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In this study, we report that RAS(ON) multi-selective inhibition led to rapid and profound PDAC regressions in immunocompetent mice, decreasing myeloid cells and increasing T cells and macrophages in the tumor microenvironment.
    explanation: >-
      Direct PDAC evidence was omitted from the immune report despite being cited in the resistance
      report.
  - reference: PMID:40057911
    reference_title: T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The depth and duration of tumor regression depended on T cells and conventional dendritic cells.
    explanation: >-
      Depletion/genetic experiments establish immune contribution in mouse PDAC.
  notes: >-
    Both July OpenScientist reports and their updated assessments now sit under kb/hypotheses/Pancreatic_Ductal_Adenocarcinoma
    after consolidation into this disease. PMID40057911 was already available when the immune report
    omitted it; the August 2026 CTLA-4/Treg study is subsequent evidence.
- hypothesis_group_id: ras_on_inhibitor_acquired_resistance
  hypothesis_label: Acquired Resistance to RAS(ON) Multiselective Inhibition
  status: EMERGING
  description: >-
    Daraxonrasib resistance includes clinical KRAS amplification and other RAS-pathway alterations,
    with mutant-allele assignment inferred by an exploratory variant-allele-frequency method.
    Preclinical and limited clinical findings support RTK bypass, MYC-related programs and allele-specific
    cyclophilin-A or EGFR/wild-type-RAS routes. The 44-patient paired ctDNA study updates the July
    report: patient mechanisms are no longer wholly unknown, but selected-cohort frequencies, non-genomic
    routes, pre-existing versus newly selected clones and optimal salvage remain unresolved. Distinct
    inhibitor classes and combination regimens must be kept explicit.
  evidence:
  - reference: PMID:42581230
    reference_title: Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we report mechanisms of acquired resistance to daraxonrasib monotherapy observed through targeted sequencing of over 800 genes in paired pretreatment and end of treatment circulating tumor DNA samples from 44 patients in the phase 1/2 clinical trial.
    explanation: >-
      August 2026 paired clinical sequencing supersedes the July reports and earlier assessment claim
      that no longitudinal clinical characterization was available.
  - reference: PMID:42581230
    reference_title: Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26 of 44; 59%) of these patients, including, most notably, mutant KRAS amplifications in one-third (16 of 44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4 of 44; 9%), MAPK (11 of 44; 25%) and PI3K (4 of 44; 9%) pathways.
    explanation: >-
      Frequencies apply to 44 profiled patients with prior disease control followed by progression,
      not all treated PDAC patients; categories overlap. Mutant-allele attribution from ctDNA is
      exploratory and unconfirmed, as specified in Supplementary Table 3.
diagnosis:
- name: Pancreatic-Protocol Cross-Sectional Imaging
  description: >-
    Multiphasic contrast-enhanced CT establishes lesion anatomy, vascular involvement and metastatic
    extent. MRI is an alternative or problem-solving examination; resectability requires multidisciplinary
    interpretation.
  evidence:
  - reference: PMID:41067164
    reference_title: Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with pancreatic cancer.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Multiphasic contrast-enhanced thoracic-abdominal and pelvic CT, including late arterial phase and portal venous phase, should be used as the first-line imaging modality for suspected pancreatic cancer
    explanation: >-
      Defines first-line diagnostic imaging.
- name: Tissue Diagnosis
  description: >-
    Cytology or biopsy, preferably by endoscopic-ultrasound guidance where appropriate, confirms
    malignancy before systemic therapy. Tissue morphology and clinical imaging must be reconciled
    with the differential diagnosis.
  evidence:
  - reference: PMID:41067164
    reference_title: Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with pancreatic cancer.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Cytology or biopsy proof of pancreatic cancer should be obtained before initiation of ChT in localised disease, preferably by EUS guidance
    explanation: >-
      Specifies tissue confirmation before chemotherapy.
- name: Germline and Tumor Molecular Testing
  description: >-
    Inherited susceptibility testing and tumor profiling identify clinically relevant BRCA, mismatch-repair
    and other actionable alterations. KRAS-wild-type tumors particularly warrant a search for alternative
    drivers, including fusions; the result must match the treatment-specific evidence.
  evidence:
  - reference: PMID:41067164
    reference_title: Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with pancreatic cancer.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: BRCA genetic testing should be offered to all patients with metastatic pancreatic cancer
    explanation: >-
      Supports germline testing in metastatic disease.
animal_models:
- name: Immunocompetent Mouse PDAC RAS-Inhibition Models
  species: Mouse
  genotype: KRAS-driven autochthonous and syngeneic PDAC systems
  description: >-
    RMC-7977 and daraxonrasib experiments test tumor regression, immune-cell changes and immunotherapy
    combinations in immunocompetent PDAC. Results depend on regimen and tumor/host model and do not
    establish patient immune pharmacodynamics.
  publication: PMID:40057911
  modeled_mechanisms:
  - target: Immunosuppressive TME Reversibility under RAS(ON) Inhibition
    relationship: PERTURBS
    description: Measures immune remodeling and depletion-defined immune contribution.
    limitations: Mouse immune ecosystems and drug exposures differ from human metastatic disease.
  evidence:
  - reference: PMID:40057911
    reference_title: T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In this study, we report that RAS(ON) multi-selective inhibition led to rapid and profound PDAC regressions in immunocompetent mice, decreasing myeloid cells and increasing T cells and macrophages in the tumor microenvironment.
    explanation: >-
      Direct PDAC evidence was omitted from the immune report despite being cited in the resistance
      report.
- name: KPC RMC-7977 Acquired-Resistance Models
  species: Mouse
  genotype: Kras/Trp53-driven genetically engineered pancreatic cancer
  description: >-
    Chronic RMC-7977 exposure produces initially responding and subsequently relapsing KPC tumors.
    MYC and YAP/TEAD programs were interrogated; tool-compound models and clinical daraxonrasib cohorts
    have different resistance distributions.
  publication: PMID:38588697
  modeled_mechanisms:
  - target: MYC Amplification-Driven RAS-Independent Proliferation
    relationship: PERTURBS
    description: Tracks relapse-associated MYC amplification and downstream bypass.
    limitations: Selected mouse tumors do not estimate patient route prevalence.
  evidence:
  - reference: PMID:38588697
    reference_title: Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro.
    explanation: >-
      Primary 2024 RMC-7977 study supplies stronger support than the systematic review cited by OpenScientist.
experimental_models:
- name: Human PDAC Cell and Organoid RAS-Response Models
  experimental_model_type: ORGANOID
  description: >-
    Patient-derived PDAC organoids and established cell models permit driver-specific RMC-7977 sensitivity
    assays; engineered and selected cell models test bypass mechanisms. These isolated epithelial
    systems do not reproduce the complete immune or desmoplastic microenvironment.
  publication: PMID:38588697
  modeled_mechanisms:
  - target: KRAS Oncogene Activation
    relationship: PERTURBS
    description: Tests RAS-GTP-inhibitor signaling and growth response.
    limitations: Cell viability and target phosphorylation are not patient response or immune-remodeling endpoints.
  evidence:
  - reference: PMID:38588697
    reference_title: Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: RMC-7977 exhibited low nanomolar potency on the viability of most human and mouse PDAC cell lines and human PDAC organoids
    explanation: >-
      Direct cell and organoid assays establish activity with subtype/driver variation, not whole-organism
      immunity.
updated_date: '2026-09-05T00:50:17Z'

📚

References & Deep Research

References

DOI:10.1146/annurev-pathmechdis-031621-024600

Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance

1 finding

PDAC has a prominent and spatially heterogeneous stromal microenvironment that meaningfully shapes treatment resistance.

"Pancreatic ductal adenocarcinoma (PDAC) features a prominent stromal microenvironment with remarkable cellular and spatial heterogeneity that meaningfully impacts disease biology and treatment resistance."

DOI:10.1158/2159-8290.CD-23-0428

Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer

1 finding

Functionally distinct fibroblast states are part of the immunosuppressive circuitry of pancreatic cancer.

"Senescence defines a distinct subset of myofibroblasts that orchestrates immunosuppression in pancreatic cancer."

DOI:10.1001/jamaoncol.2024.1930

Pancreatic Cancer Surveillance and Survival of High-Risk Individuals

1 finding

Observational surveillance of high-risk individuals associated detection with earlier stage and longer survival; selection and lead-time limitations prevent interpreting this as randomized population-screening benefit.

DOI:10.1038/s41467-023-40727-7

Single cell transcriptomic analyses implicate an immunosuppressive tumor microenvironment in pancreatic cancer liver metastasis

1 finding

Single-cell profiling characterizes immunosuppressive populations in pancreatic-cancer liver metastases. Observational cell-state associations do not establish universal resistance to all targeted and immune therapies.

DOI:10.1038/s41591-024-03075-7

Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer

1 finding

A multiparameter premetastatic-liver study links tissue features with subsequent metastatic outcome; predictive associations are not proof of each niche mechanism or a broadly validated clinical diagnostic test.

DOI:10.1136/jitc-2021-004485

Detection of microsatellite instability-high (MSI-H) by liquid biopsy predicts robust and durable response to immunotherapy in patients with pancreatic cancer

1 finding

Liquid-biopsy-selected MSI-high pancreatic cancer showed immunotherapy activity in a small retrospective series; seven responses among nine evaluable patients cannot be generalized to unselected PDAC.

DOI:10.1186/s12943-024-02003-0

Single-cell transcriptome analysis reveals subtype-specific clonal evolution and microenvironmental changes in liver metastasis of pancreatic adenocarcinoma and their clinical implications

1 finding

Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes.

"Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes."

Show evidence (1 reference)

DOI:10.1186/s12943-024-02003-0 SUPPORT Human Clinical

"Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes."

Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.

DOI:10.1200/jco.21.01604

Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer

1 finding

Final POLO follow-up did not show statistically significant overall-survival improvement despite the previously demonstrated maintenance progression-free-survival benefit.

DOI:10.12688/f1000research.21981.1

Recent advances in the treatment of pancreatic cancer

1 finding

Historical treatment review supplies background; contemporary regimen efficacy is grounded in the primary randomized trials elsewhere in the model.

DOI:10.3322/caac.21820

Cancer statistics, 2024

1 finding

Population cancer statistics concern calendar-year and disease-site groupings; all-pancreatic-cancer survival is not an interchangeable PDAC stage-specific estimate.

DOI:10.3390/curroncol31090385

Systemic Therapy for Metastatic Pancreatic Cancer—Current Landscape and Future Directions

1 finding

Review of systemic therapy and molecularly selected treatment strategies; individual trial outcomes are verified against the primary publications.

DOI:10.3390/onco5030037

Pancreatic Cancer: Epidemiology, Risk Factors, and Prevention

1 finding

Review of epidemiology and risk factors; modifiable-risk associations and proposed screening/prevention strategies are distinguished from proven individual molecular causes.

DOI:10.1038/s41467-026-75960-3

Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer