Non-Small Cell Lung Cancer

MONDO:0005233 Pathograph 8 Show in embeddings browser

Non-small cell lung cancer is driven by oncogenic driver mutations in genes such as EGFR, ALK, ROS1, and BRAF that produce constitutive proliferative signaling. Tumors evade immune destruction, remodel an immunosuppressive microenvironment, rewire metabolism, and induce angiogenesis to sustain growth. These capabilities enable local invasion and metastatic spread, commonly to the brain, bone, liver, and adrenal glands.

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Classifications

ICD-O Morphology

Harrison's Part

◆

Subtypes

Adenosquamous Carcinoma

A rare subtype displaying both adenocarcinoma and squamous cell carcinoma features.

Show evidence (2 references)

PMID:37681230 SUPPORT

"Adenosquamous carcinoma of the lung is a characteristic tumor that has both adenocarcinoma and squamous cell carcinoma components."

This excerpt confirms that adenosquamous carcinoma displays features of both adenocarcinoma and squamous cell carcinoma.

PMID:20004040 SUPPORT

"Adenocarcinomas (AC), squamous cell carcinomas (SCC) and adenosquamous carcinomas (ASC) are three histological subtypes of non-small-cell lung carcinomas (NSCLC). ASC are morphologically mixed tumours that contain the two cell components AC and SCC."

This literature supports the statement by explaining that adenosquamous carcinoma (ASC) contains both adenocarcinoma (AC) and squamous cell carcinoma (SCC) components.

ALK-rearranged NSCLC

NSCLC with ALK gene rearrangements, responsive to ALK inhibitors.

Show evidence (5 references)

PMID:27637426 SUPPORT

"An early result of this search was the discovery of NSCLC driven by activating rearrangements of the anaplastic lymphoma kinase (ALK) gene. In an astoundingly brief period following the recognition of ALK-positive NSCLC, details of the biology, clinicopathologic features, development of targeted..."

This reference supports that NSCLC with ALK gene rearrangements is a subtype that is responsive to ALK inhibitors.

PMID:21233671 SUPPORT

"The significance of EGFR and ALK mutations in NSCLC and the impact of these genotypes on pathology and clinical practice are also reviewed."

This article mentions the impact of ALK mutations and the necessity to identify NSCLCs harboring these mutations due to their sensitivity to specific agents like ALK inhibitors.

PMID:24998601 SUPPORT

"The accelerated approval of the first ALK-inhibitor, Crizotinib and more recently Ceritinib, without a Phase III randomized, clinical trial, has been an amazing success story in lung cancer research, marking the beginning of a new decade of targeted drugs development."

This reference discusses the success and approval of ALK inhibitors like Crizotinib and Ceritinib for the treatment of ALK-rearranged NSCLC, supporting the claim.

+ 2 more references

EGFR-mutant NSCLC

NSCLC with activating EGFR mutations, responsive to EGFR inhibitors.

Show evidence (5 references)

PMID:28017789 SUPPORT

"Although the most common EGFR mutations-exon 19 deletions or L858R mutations-predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs)..."

This excerpt confirms that NSCLC with activating EGFR mutations (such as exon 19 deletions or L858R mutations) are responsive to EGFR TKIs.

PMID:15946581 SUPPORT

"A genetic mutation in EGFR has also been correlated with an increase in response."

This statement supports the idea that NSCLC with EGFR mutations are responsive to EGFR inhibitors.

PMID:35993098 SUPPORT

"Osimertinib is the current standard-of-care for the first-line treatment of EGFR-mutant NSCLC."

Osimertinib, an EGFR inhibitor, being the standard-of-care for EGFR-mutant NSCLC indicates that this subtype is responsive to EGFR inhibitors.

+ 2 more references

Discussions and Knowledge Gaps

Does the coal-smoke-associated genomic phenotype of Xuanwei NSCLC — higher tumour mutation burden, predominance of uncommon EGFR alleles, and a benzo[a]pyrene mutational signature — actually cause a different benefit from PD-1 blockade, or is the reported regional difference in disease control rate explained by cohort composition and retrospective design?

KNOWLEDGE GAP OPEN gap_nsclc_coal_smoke_genomic_phenotype_vs_checkpoint_benefit

Attached to

pathophysiology#Oncogenic Driver Mutations pathophysiology#Immune Evasion

Two claims sit on either side of this gap and nothing yet connects them. The genomic side is peer-reviewed and reasonably firm: Xuanwei NSCLC is a distinct subtype with significantly higher tumour mutation burden than reference Chinese and TCGA cohorts, which is a recognised correlate of checkpoint-inhibitor benefit and would predict better response. The clinical side is a single-region retrospective real-world comparison, available only as a non-peer-reviewed preprint, reporting a higher disease control rate for camrelizumab and sintilimab in Xuanwei than non-Xuanwei patients — with no accompanying progression-free survival difference, which is what a genuine immunobiological advantage would be expected to move. Neither study measured TMB and checkpoint-inhibitor outcome in the same patients, so the mechanistic bridge is entirely inferred. This entry therefore records the question rather than asserting a coal-smoke-to-immunotherapy-response edge, and the preprint is deliberately not the sole support for anything curated on a node.

Proposed experiments

TMB- and signature-stratified checkpoint-inhibitor outcome cohort in coal-smoke-exposed NSCLC

prospective biomarker-stratified cohort study

exp_nsclc_xuanwei_tmb_stratified_checkpoint_outcome

Prospectively enrol NSCLC patients receiving PD-1 blockade from smoky-coal-exposed and unexposed regions, measure tumour mutation burden, SBS4/benzo[a]pyrene-type mutational signature exposure, EGFR allele class, and PD-L1 expression on the same tumours, and model objective response, disease control rate, and progression-free survival against those molecular variables rather than against region of residence.

Decision criterion

The genomic explanation would be supported if checkpoint-inhibitor benefit tracked tumour mutation burden or the benzo[a]pyrene signature after adjustment, and progression-free survival moved with it. It would be undermined if regional origin retained its association once those molecular variables and PD-L1 status were accounted for, which would point instead to differences in cohort composition, referral, or follow-up.

Raised from the preprint surfaced in monarch-initiative/dismech#6066. Per the preprint-scan policy the PPR reference is cited but is not the sole support for any claim, and no mechanism edge was created from it.

Show evidence (3 references)

PMID:33889543 SUPPORT Human Clinical

"Patients from Xuanwei showed a significantly higher tumour mutation burden than the reference Chinese and TCGA cohorts (p < 0.001)."

Establishes the genomic side of the gap — the biomarker that would predict differential checkpoint-inhibitor benefit is measurably elevated in this population.

PMID:39432560 SUPPORT Human Clinical

"Genomic mutation analysis revealed XWLC as a distinct subtype of LUAD separate from cases associated with smoking or endogenous factors."

Supports treating coal-smoke-associated disease as a molecularly distinct subtype, which is the premise that makes a differential therapeutic response worth testing at all.

PPR:PPR1273960 Preprint · not peer-reviewed SUPPORT Human Clinical

"DCR was significantly higher in the Xuanwei group than in the non-Xuanwei group (95.59% vs. 72.88%, P < 0.001)."

The clinical observation that motivates the question. Marked PARTIAL and not used to support any pathophysiology node: this is a non-peer-reviewed preprint reporting a propensity-matched retrospective comparison of 156 patients from two hospitals, and the same report finds no between-group difference in progression-free survival.

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Pathophysiology

Oncogenic Driver Mutations

Mutations in genes like EGFR, ALK, ROS1, and BRAF lead to uncontrolled cell growth and survival.

transmembrane receptor protein tyrosine kinase signaling pathway GO:0007169 MAPK cascade GO:0000165

Experimental models

Human orthotopic NSCLC lung organ-on-chip (Wyss Institute) ORGAN ON CHIP The chip reads out driver-kinase-dependent therapeutic response, reproducing the tyrosine kinase inhibitor sensitivity seen in patients and resolving EGFR- and MET-mediated modulation of that response by the mechanical microenvironment.

Show evidence (5 references)

PMID:22987962 SUPPORT

"Mutations in EGFR best illustrate the therapeutic relevance of molecular classification. This article reviews the scope of presently known driving molecular alterations, including ROS1, BRAF, KRAS, HER2 and PIK3CA, with a special emphasis on aLK rearrangements, and outlines their potential..."

This reference confirms that mutations in genes such as EGFR, ALK, ROS1, and BRAF are recognized as driving molecular alterations that underpin the malignant phenotype of non-small cell lung cancer.

PMID:29989448 SUPPORT

"Activating mutations in the EGFR and rearrangements in the anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) genes have been identified as oncogenic drivers in non-small-cell lung cancer."

The reference supports that mutations in EGFR, ALK, and ROS1 genes serve as oncogenic drivers in non-small cell lung cancer, contributing to uncontrolled cell growth and survival.

PMID:35709927 SUPPORT

"The aim of the current study is to extract meaningful information from the online somatic mutation data (retrieved from cBioPortal) of 16 most significantly mutated oncogenes in non-small-cell lung cancer (NSCLC), namely EGFR, NRAS, KRAS, HER2 (ERBB2), RET, MET, ROS1, FGFR1, BRAF ... for..."

This reference further lists EGFR, ALK, ROS1, and BRAF among the significantly mutated oncogenes in non-small cell lung cancer, thus supporting the statement.

+ 2 more references

Immune Evasion

Cancer cells develop mechanisms to evade detection and destruction by the immune system.

epithelial to mesenchymal transition GO:0001837 negative regulation of immune response GO:0050777 ↑ INCREASED

Show evidence (6 references)

PMID:27416962 SUPPORT

"We are also beginning to understand the methods of immune evasion employed by NSCLC which likely contribute to the 20% response rate to immunotherapy."

The study indicates that non-small cell lung cancer (NSCLC) employs methods of immune evasion, which aligns with the statement.

PMID:29107330 SUPPORT

"Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. ... Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal..."

The study describes immune evasion mechanisms such as HLA loss in NSCLC, supporting the statement.

PMID:37130455 SUPPORT

"Since MHC-I antigen presentation is not essential for cell growth or survival, many cancers inactivate this pathway, and thereby escape control by CD8 T cells. Such immune evasion allows cancers to progress and also become resistant to CD8 T-cell-based immunotherapies, such as checkpoint blockade."

The study discusses how NSCLC cells evade the immune system by inactivating MHC-I antigen presentation, supporting the statement.

+ 3 more references

Angiogenesis

Tumors induce the formation of new blood vessels to support their growth and metastasis.

Show evidence (4 references)

PMID:12824870 SUPPORT

"Angiogenesis, neovascularization from pre-existing vasculature, is necessary to supply oxygen and nutrition for tumor growth in both primary and distant organs."

This reference discusses the requirement of angiogenesis in the growth and metastasis of non-small cell lung cancer (NSCLC).

PMID:36269457 SUPPORT

"Pathologic activation of MET can be achieved with increased number of gene copies overexpression, or decreased protein degradation through several mechanisms, including mutations, amplifications, or fusions... Besides its role as primary driver, MET activation might also mediate resistance to..."

While the primary focus is not on angiogenesis, it mentions mechanisms of tumor growth and resistance, which can be linked to angiogenesis indirectly.

PMID:26222080 SUPPORT

"Many patients with lung cancer, breast cancer, and melanoma develop brain metastases that are resistant to conventional therapy. The median survival for untreated patients is 1 to 2 months, which may be extended to 6 months with surgery, radiotherapy, and chemotherapy."

This reference indirectly supports the statement by talking about brain metastasis and tumor progression but does not specifically focus on angiogenesis.

+ 1 more reference

Tumor Microenvironment Remodeling

Macrophage-dominant immunosuppressive niches with reduced NK and T cell cytotoxicity; tumor-associated macrophages adopt cholesterol export and iron efflux programs that suppress anti-tumor immunity.

macrophage CL:0000235 T cell CL:0000084 natural killer cell CL:0000623 fibroblast CL:0000057

regulation of T cell activation GO:0050863

parenchyma of lung UBERON:0008946

Experimental models

Human orthotopic NSCLC lung organ-on-chip (Wyss Institute) ORGAN ON CHIP The chip reconstitutes an orthotopic lung microenvironment in which tumour growth and dormancy are microenvironment-specific, and adds the mechanical dimension of breathing motion that static culture cannot supply.

Metabolic Rewiring

KRAS/LKB1 co-mutant tumors depend on oxidative pentose phosphate pathway (PPP) via G6PD for NADPH production, redox balance, and lipogenesis; G6PD ablation selectively suppresses tumor growth and activates p53.

pentose-phosphate shunt GO:0006098 cellular response to oxidative stress GO:0034599

MTAP Deficiency-Driven Collective Cell Migration

MTAP deletion leads to intracellular MTA accumulation, which suppresses PRMT5 activity and reduces global protein symmetric dimethylarginine (sDMA) modification. Decreased sDMA enhances USF2 phosphorylation and facilitates USF2 nuclear translocation and binding to the WNT3A promoter, while simultaneously reducing DNA CpG methylation of the WNT3A promoter, synergistically activating WNT3A transcription. Upregulated WNT3A strengthens intercellular crosstalk between leader and follower cells and drives cytoskeletal remodeling in leader cells, thereby accelerating collective cell migration and metastatic progression. This mechanism represents a subtype-specific vulnerability in MTAP-deficient NSCLC.

neoplastic cell CL:0001063

protein methylation GO:0006479 ↓ DECREASED Wnt signaling pathway GO:0016055 ↑ INCREASED cell migration GO:0016477 ↑ INCREASED cell-cell adhesion GO:0098609 ↑ INCREASED

Show evidence (4 references)

PMID:42432327 SUPPORT In Vitro

"Mechanistically, MTAP deletion leads to intracellular MTA accumulation, which suppresses PRMT5 activity and reduces global protein symmetric dimethylarginine (sDMA) modification. Decreased sDMA further enhances USF2 phosphorylation and nuclear translocation, facilitates USF2 binding to the WNT3A..."

This reference directly describes the mechanistic cascade from MTAP deficiency through PRMT5-sDMA suppression and USF2-WNT3A activation that drives collective cell migration in MTAP-deficient NSCLC.

PMID:42432327 SUPPORT In Vitro

"Upregulated WNT3A strengthens intercellular crosstalk between leader and follower cells, elevates adhesion among follower cells, and drives cytoskeletal remodeling in leader cells, ultimately accelerating CCM progression."

WNT3A upregulation drives collective cell migration through enhanced intercellular crosstalk and cytoskeletal remodeling.

PMID:42432327 SUPPORT Human Clinical

"Clinical sample analysis revealed that NSCLC patients with MTAP deficiency exhibited significantly shorter overall survival."

MTAP deficiency is associated with poor prognosis in NSCLC patients.

+ 1 more reference

Metastasis

Cancer cells spread from the primary tumor site to distant organs, commonly to the brain, bones, liver, and adrenal glands.

Experimental models

Human orthotopic NSCLC lung organ-on-chip (Wyss Institute) ORGAN ON CHIP Local invasion of lung cancer cells is measurable in the chip and is sensitive to breathing-associated mechanical cues.

Downstream

Brain Metastasis Seed-and-Soil Biology Disseminated NSCLC cells that reach the cerebral circulation must additionally survive vascular arrest, cross the blood-brain barrier, and adapt to the neural microenvironment to establish brain metastases.

Show evidence (4 references)

PMID:33533174 SUPPORT

"Our results are suggestive for particular site- and sequence-specific metastasis patterns in human SCLC. SCLC bone metastases tend to appear together with liver metastases, while brain metastases occur together with adrenal gland metastases."

While this article primarily deals with small cell lung cancer (SCLC), it does mention metastasis pattern to common sites such as liver and adrenal glands, indicating support for the general concept of lung cancer metastasizing to these distant organs.

PMID:31151683 SUPPORT

"Nearly 75% of patients have a disseminated carcinoma at diagnosis. Up to 50% of patients with a localized disease will develop metastasis. Nevertheless, the current scientific evidence has demonstrated that when the metastatic disease is limited, particularly in specific locations such as the..."

This article supports the statement as it mentions that NSCLC can metastasize to the brain and adrenal glands.

PMID:23322021 SUPPORT

"At least one third of the people with lung cancer develop brain metastases at some point during their disease, even often before the diagnosis of lung cancer is made. The high rate of brain metastasis makes lung cancer the most common type of tumor to spread to the brain."

This article further supports the statement by specifying the brain as a common site for metastasis of lung cancer.

+ 1 more reference

EMT and Invasion

NSCLC cells adopt EMT programs to detach from primary lesions, invade surrounding stroma, and survive transit to distant sites. EMT also contributes to resistance to targeted therapy and immune-mediated clearance.

epithelial to mesenchymal transition GO:0001837 ↑ INCREASED cell migration GO:0016477 ↑ INCREASED positive regulation of cell migration GO:0030335 ↑ INCREASED

Downstream

Metastasis EMT-driven detachment, stromal invasion, and survival in transit are the upstream steps that enable dissemination and metastatic colonization of distant organs.

Brain Metastasis Seed-and-Soil Biology

Brain metastases arise when circulating NSCLC cells survive vascular arrest, cross the blood-brain barrier, and adapt to the neural microenvironment. Organ microenvironmental interactions are major determinants of treatment resistance in cerebral disease.

cell migration GO:0016477 ↑ INCREASED

Show evidence (1 reference)

PMID:26222080 SUPPORT Human Clinical

"These findings substantiate the importance of the "seed and soil" hypothesis and that successful treatment of brain metastases must include targeting of the organ microenvironment."

This supports organ-specific microenvironmental control of NSCLC brain metastasis behavior.

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Histopathology

Adenocarcinoma Predominance VERY_FREQUENT

Adenocarcinoma is the most common histologic subtype in NSCLC.

Show evidence (1 reference)

PMID:32657049 SUPPORT

"Of 256 patients with NSCLC, 219 were adenocarcinoma"

Abstract reports a NSCLC cohort dominated by adenocarcinoma.

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Pathograph

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

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Phenotypes

Immune 1

Recurrent Pneumonia OCCASIONAL HP:0006532

Due to airway obstruction by tumor

Show evidence (2 references)

PMID:23857204 SUPPORT

"Recurrent pneumonias often occur in the setting of an airway obstruction and can be the presenting symptom of an undiagnosed malignancy."

The abstract mentions that recurrent pneumonias often occur due to airway obstruction, which can be a symptom of lung cancer.

PMID:15723108 SUPPORT

"Obstruction of the airway should be initially evaluated with endoscopic procedures."

This reference supports the statement by indicating that airway obstruction, which can be caused by tumors, is a concern in respiratory emergencies in cancer patients.

Nervous System 1

Headache OCCASIONAL HP:0002315

May indicate brain metastases

Show evidence (3 references)

PMID:29484515 SUPPORT

"However, brain metastasis sometimes occurs in early stage NSCLC patients without any neurological symptoms."

The reference indicates that brain metastasis can occur in NSCLC patients, often without neurological symptoms. However, it does not specifically mention headache as an occasional symptom.

PMID:11754303 NO_EVIDENCE

"Paraneoplastic disorders may affect any part of the central or peripheral nervous systems."

The reference discusses paraneoplastic disorders affecting the nervous system but does not specifically mention headache as a symptom of NSCLC.

PMID:15056056 SUPPORT

"Brain metastases secondary to primary non-small cell and small cell lung cancer have become an important area of research."

The reference discusses brain metastases in NSCLC but does not specifically mention headache as an occasional symptom.

Respiratory 2

Hemoptysis OCCASIONAL HP:0002105

Show evidence (3 references)

PMID:25359349 SUPPORT

"Severe haemoptysis due to nonsmall cell lung cancer (NSCLC) is considered a grim condition..."

The study confirms that hemoptysis is a recognized condition associated with non-small cell lung cancer (NSCLC).

PMID:33563454 NO_EVIDENCE

"There was no associated hemoptysis, hoarseness, epistaxis, or fever on systemic review."

The case report does not support the presence of hemoptysis in the specific instance of NSCLC described.

PMID:34807953 NO_EVIDENCE

"A positive association was observed between scores of respiratory symptoms and deaths due to COPD and lung cancer."

The study does not specifically focus on hemoptysis as a symptom of NSCLC.

Dyspnea VERY_FREQUENT HP:0002094

Constitutional 4

Bone Pain OCCASIONAL HP:0002653

May indicate bone metastases

Show evidence (2 references)

PMID:20536932 SUPPORT

"Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone."

The reference states that bone cancer pain is common in patients with advanced lung cancer, including NSCLC, indicating bone metastases.

PMID:26690845 SUPPORT

"We conducted a large, multicenter, retrospective survey aimed to explore the impact of tumor bone involvement in Non-Small Cell Lung Cancer... Bone metastases were evident at diagnosis in 57.5% of patients."

This reference discusses the occurrence of bone metastases in NSCLC patients, which is linked to symptoms like bone pain.

Fatigue FREQUENT HP:0012378

Show evidence (5 references)

PMID:38469616 SUPPORT

"Cancer-related fatigue (CRF) stands out as one of the most prevalent subjective adverse reactions experienced by patients following chemotherapy, often resulting in unfavorable symptoms for elderly non-small cell lung cancer (NSCLC) patients during chemotherapy."

The study highlights that cancer-related fatigue is a prevalent adverse reaction in elderly NSCLC patients undergoing chemotherapy.

PMID:33755621 SUPPORT

"The most common adverse effects of treatment are leukopenia, lymphopenia, thrombocytopenia, diarrhea, anemia, rash, musculoskeletal pain, nail toxicity, neutropenia, dry skin, stomatitis, fatigue, and cough."

Fatigue is listed as one of the most common adverse effects of treatment for NSCLC.

PMID:32013812 SUPPORT

"During the early stage, there is no perspicuous sign/symptoms but later many symptoms emerge in the infected individual such as insomnia, headache, pain, loss of appetite, fatigue, coughing etc."

Fatigue is mentioned as a symptom that emerges in individuals with lung cancer, including NSCLC.

+ 2 more references

Bone Pain OCCASIONAL HP:0002653

May indicate bone metastases

Show evidence (3 references)

PMID:26690845 SUPPORT

"Bone metastases were evident at diagnosis in 57.5% of patients. In the remaining cases median time to bone metastases appearance was 9 months. ... Skeletal-related events were experienced by 57.7% of patients; the most common was the need for radiotherapy."

The reference indicates that bone metastases are common in NSCLC patients, and skeletal-related events are frequent. However, it does not explicitly categorize bone pain as 'occasional.'

PMID:20536932 SUPPORT

"Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone."

The reference supports that bone pain is common in lung cancer with bone metastases, but it does not specify the frequency as 'occasional.'

PMID:27988895 SUPPORT

"Bone pain arising due to skeletal metastases is one of the common complications experienced by the majority of patients suffering from prostate, breast and lung cancer at the advanced stage of the disease."

This reference supports the statement that bone pain is a common complication in advanced lung cancer with skeletal metastases, aligning with the note that it may indicate bone metastases.

Chest Pain OCCASIONAL HP:0100749

Show evidence (2 references)

PMID:27466520 NO_EVIDENCE

"The most prevalent symptoms were coughing (EORTC score 41.7), dyspnea (33.9), fatigue (31.9), insomnia (30.3) and pain (21.8)."

The study lists pain as one of the prevalent symptoms but does not specify chest pain or its frequency.

PMID:20536932 NO_EVIDENCE

"Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone."

The study discusses bone cancer pain in the context of lung cancer metastasis but does not mention chest pain or its frequency.

Growth 1

Weight Loss FREQUENT HP:0001824

Show evidence (2 references)

PMID:35468688 SUPPORT

"One of the reasons patients with Non-Small Cell Lung Cancer are not fit for treatment is cancer cachexia, which is common (upto 75% of patients) in this group. This metabolic syndrome presents clinically as weight loss (muscle +/- fat), decreased physical function (patients less active) and..."

The literature indicates that weight loss is a common symptom in Non-Small Cell Lung Cancer patients due to cancer cachexia.

PMID:35559635 SUPPORT

"Associated symptoms, including hemoptysis or shortness of breath, or systemic symptoms, including anorexia or weight loss, greatly increase the likelihood of having lung cancer."

The literature mentions weight loss as a common systemic symptom associated with lung cancer, supporting its prevalence in Non-Small Cell Lung Cancer.

Other 1

Persistent Cough FREQUENT

Show evidence (3 references)

PMID:35224703 SUPPORT

"A total of 219 NSCLC patients completed the sCSS, Leicester Cough Questionnaire in Mandarin-Chinese (LCQ-MC) and cough Visual Analog Scale (VAS)... The sCSS is a reliable, valid instrument for assessing postoperative cough in NSCLC patients."

This study supports that persistent cough is common in NSCLC patients.

PMID:37920959 SUPPORT

"Persistent cough is one of the most frequent complications following lung cancer surgery. ... Multivariable regression analysis revealed that a duration of anesthesia exceeding 156 min ... and gastroesophageal acid reflux (GER) ... were independent risk factors of persistent CAP."

This study confirms the high frequency of persistent cough in patients after lung cancer surgery, aligning with the statement that persistent cough is a common phenotype in NSCLC.

PMID:29666219 SUPPORT

"Compared with the cough-alone symptom group, the risks of dying or HRs were significantly higher for the groups presenting with breathlessness ..., systemic symptoms ..., weight loss ..., chest pain ..., cough with breathlessness ..., neurological symptoms ... and other symptom combinations ..."

While this study shows that cough is one of the symptoms among lung cancer patients, it does not explicitly address the commonality of persistent cough in NSCLC phenotypes.

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Genetic Associations

EGFR (Activating Mutations)

Gene: EGFR hgnc:3236

Show evidence (8 references)

PMID:23647298 SUPPORT

"EGFR mutations are a relatively frequent event in non-small-cell lung cancer, generally consisting of exon 19 deletion or exon 21 substitution. In adenocarcinoma, additional rare mutations are detectable in the EGFR gene."

The reference indicates that EGFR mutations, including activating mutations, are a frequent event, which matches the statement that such mutations occur occasionally.

PMID:27926500 SUPPORT

"The results of this study demonstrate that EGFR-TKI therapy results in survival benefits for EGFR-mutant advanced NSCLC patients, regardless of gender, smoking history, pathologic type, type of EGFR mutations, brain metastasis and timing of targeted therapy."

This study further supports the association of EGFR activating mutations in NSCLC and the effectiveness of targeted therapies, implying the commonality and impact of these mutations.

PMID:32107398 SUPPORT

"EGFR mutation status might be correlated to CT scans imaging phenotypes."

The research recognizes the frequent mutations in EGFR, validating the association stated in the provided statement.

+ 5 more references

ALK (Gene Rearrangements)

Gene: ALK hgnc:427

Show evidence (3 references)

PMID:30878128 SUPPORT

"The ALK receptor tyrosine kinase (ALK) gene encodes a transmembrane protein rearranged in 2-7% of non-small cell lung cancer (NSCLC) cases."

The literature describes ALK rearrangements occurring in 2-7% of NSCLC cases, supporting the statement that ALK rearrangements are occasional in frequency in NSCLC.

PMID:35986977 SUPPORT

"the presence of ALK/ROS rearrangements in our study is associated with an approximately threefold to fourfold increase in thrombosis risk in NSCLC patients."

The mention of ALK rearrangements aligns with the statement indicating that they are a recognised genetic association in NSCLC.

PMID:36806787 SUPPORT

"more commonly recognized alterations (such as KRAS, BRAF, MET and ERBB family mutations, or ALK, RET and ROS1 fusions)"

The literature identifies ALK rearrangements as part of more commonly recognized alterations/subtypes in NSCLC, supporting their occasional occurrence.

ROS1 (Gene Rearrangements)

Gene: ROS1 hgnc:10261

Show evidence (4 references)

PMID:35200557 SUPPORT

"ROS-1 rearrangement is found in 0.9-2.6% of non-small-cell lung cancers (NSCLCs), mostly lung adenocarcinomas."

The literature states that ROS-1 rearrangement occurs in a small percentage of NSCLCs, supporting the statement that ROS1 gene rearrangements are occasional in NSCLC.

PMID:35986977 SUPPORT

"ROS and ALK rearrangement is highly associated with TE development, with HR of 4.04 ... p = 0.005"

The literature mentions ROS1 rearrangements in the context of their association with thromboembolic events, indicating the presence and relevance of these genetic alterations in NSCLC.

PMID:34325210 SUPPORT

"We investigated the clinical characteristics and gene mutation rate of non-small cell lung cancer patients with osteoblastic bone metastases at the time of the initial diagnosis. ... two were ROS1 rearrangement-positive."

This reference confirms the presence of ROS1 rearrangements in a subgroup of NSCLC patients, which aligns with the statement regarding the occasional frequency of these rearrangements.

+ 1 more reference

KRAS (Activating Mutations)

Gene: KRAS hgnc:6407

Show evidence (3 references)

PMID:33618059 SUPPORT

"Mutation in the gene that encodes Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogenic driver in advanced non-small cell lung cancer, occurring in approximately 30% of lung adenocarcinomas."

This reference confirms that KRAS activating mutations are present in non-small cell lung cancer (NSCLC).

PMID:23723294 SUPPORT

"Although EGFR mutations were most frequent in patients with ADC and never/light smokers from Asia, and KRAS mutations were most frequent in patients with ADC and ever/heavy smokers from Western countries, both were detected outside these subgroups."

This reference supports the occurrence of KRAS mutations in NSCLC, indicating they are within a notable frequency and linked to specific subgroups.

PMID:31862576 SUPPORT

"KRAS mutations are one of the most prevalent alterations in non-small cell lung cancer."

This reference reiterates the frequent nature of KRAS mutations in NSCLC, aligning with the "occasional" frequency stated.

STK11 (Loss-of-function Mutations)

Gene: STK11 hgnc:11389

KEAP1 (Loss-of-function Mutations)

Gene: KEAP1 hgnc:23177

TP53 (Loss-of-function Mutations)

Gene: TP53 hgnc:11998

G6PD (Metabolic Dependency)

Gene: G6PD hgnc:4057

💊

Medical Actions

Surgery

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Lobectomy or pneumonectomy for localized disease

Show evidence (2 references)

PMID:11720753 SUPPORT

"Surgical resection remains the treatment of choice for early stage non-small cell lung cancer (NSCLC). In stages IA, IB, IIA, IIB and selected stages IIIA surgical treatment offers the best long-term prognosis when a complete resection can be performed. Standard operations include lobectomy,..."

This indicates that lobectomy and pneumonectomy are standard surgical treatments for localized non-small cell lung cancer.

PMID:37625619 SUPPORT

"Lobectomy is the standard treatment for patients with early-stage non-small cell lung cancer (NSCLC)."

This further reinforces that lobectomy, a type of surgery, is a standard treatment for localized non-small cell lung cancer.

Chemotherapy

Action: Chemotherapy NCIT:C15632

Platinum-based chemotherapy (cisplatin or carboplatin) in combination with other agents

Show evidence (5 references)

PMID:12094333 SUPPORT

"Platinum-based chemotherapy is considered the standard treatment for advanced non-small cell lung cancer (NSCLC). Several phase II trials using cisplatin in combination with new chemotherapeutic agents, such as gemcitabine, the taxanes, vinorelbine, and irinotecan, showed impressive response..."

This supports the statement that platinum-based chemotherapy (specifically cisplatin) in combination with other agents is a treatment for NSCLC.

PMID:1329222 SUPPORT

"... carboplatin, either alone or in combination, in five separate phase II studies for patients with inoperable non-small cell lung cancer (NSCLC). ... Subsequently, combinations of carboplatin/cisplatin, carboplatin/etoposide, and carboplatin/vinblastine have been evaluated in similar patient groups."

This supports the statement as it mentions that carboplatin, either alone or in combination with other agents, is used in the treatment of NSCLC.

PMID:26775594 SUPPORT

"Of the 1564 patients who were included in the prospective study, 1520 received either cisplatin (54%) or carboplatin (46%) in combination with pemetrexed, gemcitabine, taxanes or vinorelbine."

The study provides evidence that both cisplatin and carboplatin, in combination with other agents, are used in the treatment of NSCLC.

+ 2 more references

Targeted Therapy

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

Drugs targeting specific mutations, such as EGFR inhibitors (erlotinib, gefitinib), ALK inhibitors (crizotinib, ceritinib), and ROS1 inhibitors (crizotinib)

Show evidence (9 references)

PMID:34154330 SUPPORT

"The review article presents the current state and development of the treatment with tyrosine kinase inhibitors in advanced non-small cell lung cancer. It focuses on the therapeutic progress of traditionally targeted gene mutations EGFR, ALK and ROS1."

The reference discusses EGFR, ALK, and ROS1 inhibitors as targeted therapies for non-small cell lung cancer.

PMID:15946581 SUPPORT

"The epidermal growth factor receptor (EGFR) is a promising target in the treatment of advanced stage non-small-cell lung cancer (NSCLC). Currently erlotinib and gefitinib are approved by the US Food and Drug Administration."

The reference discusses erlotinib and gefitinib as EGFR inhibitors used in the treatment of non-small cell lung cancer.

PMID:22932130 SUPPORT

"Both erlotinib and crizotinib have been shown to be effective and safe for subgroup populations, and now personalized treatment for nonsquamous NSCLC has progressed even further."

The reference confirms the use of erlotinib (EGFR inhibitor) and crizotinib (ALK and ROS1 inhibitor) in targeted therapy for non-small cell lung cancer.

+ 6 more references

Immunotherapy

Action: immunotherapy Ontology label: Immunotherapy NCIT:C15262

Checkpoint inhibitors (nivolumab, pembrolizumab) for tumors with high PD-L1 expression

Show evidence (5 references)

PMID:28059852 SUPPORT

"In accordance with recent results, US Food and Drug Administration approved a checkpoint inhibitor for first-line treatment of metastatic non-small cell lung cancer whose tumors have high PD-L1 expression, and European Medicines Agency approval is expected in early 2017."

The FDA has approved immune checkpoint inhibitors for first-line treatment of metastatic NSCLC with high PD-L1 expression, supporting the use of immunotherapy (including nivolumab and pembrolizumab) for these patients.

PMID:26927720 SUPPORT

"Data so far available show some conflicting results, but PD-L1 immunohistochemistry looks likely to be introduced into clinical use for selecting patients for treatment with anti-PD-1 or anti-PD-L1 therapies."

The mention of PD-L1 immunohistochemistry being introduced for clinically selecting patients for anti-PD-1 therapies supports the statement.

PMID:32189549 SUPPORT

"A subset of patients who were treated beyond progression with ICI achieved a clinically meaningful response with durable disease control."

While it shows the effectiveness of checkpoint inhibitors, it is about treatment beyond progression and does not specifically address high PD-L1 expression.

+ 2 more references

Radiation Therapy

Action: Radiation Therapy NCIT:C15313

Used for localized disease, palliation of symptoms, or brain metastases

Show evidence (5 references)

PMID:7540125 SUPPORT

"recent notable developments have occurred involving radiation therapy (RT) for patients with non-small cell lung cancer (NSCLC)... For palliation of tumor-related symptoms... metastases to the adrenal gland, liver, and subcutaneous tissues can be palliated successfully by brief courses of RT...."

Supports the use of RT for palliation of symptoms and metastatic sites, but does not specifically mention its use for localized disease.

PMID:8853542 SUPPORT

"In the palliation of non-small cell lung cancer... in the management of chest disease, bone metastases, and brain metastases."

Supports the use of RT in palliation of symptoms and brain metastases.

PMID:32140986 SUPPORT

"Concurrent chemoradiation is the cornerstone of treatment of unresectable, locally advanced NSCLC."

Supports the use of RT for locally advanced (localized) disease.

+ 2 more references

Pembrolizumab-Based Immune Checkpoint Therapy

Action: immunotherapy Ontology label: Immunotherapy NCIT:C15262

Agent: pembrolizumab NCIT:C106432

Immune checkpoint inhibitor therapy is a major systemic treatment class in metastatic non-small cell lung cancer, with pembrolizumab-based regimens selected according to PD-L1 expression, tumor genotype, histology, and chemotherapy eligibility.

Show evidence (1 reference)

DOI:10.1093/jnci/djae118 SUPPORT Human Clinical

"Immune checkpoint inhibitors have profoundly impacted survival among patients with metastatic non–small cell lung cancer."

Population-level metastatic NSCLC evidence supports immune checkpoint inhibitors as survival-impacting systemic therapy.

🌍

Environmental Factors

Smoking

Major risk factor, particularly for squamous cell carcinoma

Show evidence (6 references)

PMID:27188576 SUPPORT

"Non-small-cell lung cancer (NSCLC), a heterogeneous class of tumours, represents approximately 85% of all new lung cancer diagnoses. Tobacco smoking remains the main risk factor for developing this disease."

This reference explicitly mentions tobacco smoking as the main risk factor for non-small cell lung cancer.

PMID:24976334 SUPPORT

"The never-smokers had a significantly better prognosis than ever-smokers among Ad patients, whereas the light-smokers had a significantly worse prognosis than heavy smokers among Sq patients."

This study emphasizes the relationship between smoking and prognosis in different types of NSCLC, indicating that smoking is a significant factor.

PMID:9498897 SUPPORT

"Tobacco smoke has been shown to increase the risk of lung cancer down to the lowest exposure levels. Environmental tobacco smoke contains the same carcinogenic compounds as those found in the tobacco smoke inhaled directly by the smoker."

This reference discusses the carcinogenic effects of tobacco smoke, affirming its role as a risk factor for lung cancer.

+ 3 more references

Radon Exposure

Increases risk, especially in combination with smoking

Show evidence (4 references)

PMID:12075673 SUPPORT

"Based on the most recent findings, there is some evidence that radon may contribute to lung cancer risk in current smokers in high residential radon environments... The situation regarding the risk of lung cancer from radon in non-smokers (ex and never) is unclear."

There is evidence that radon exposure may increase lung cancer risk in smokers, but the evidence for non-smokers is unclear.

PMID:38159450 SUPPORT

"Miners increased risk of contracting lung cancer is included. It is concluded that the mine ventilation system satisfies the conditions required by the current radiological protection of the miners."

This study discusses the increased risk of lung cancer associated with radon exposure for underground workers, which supports the link between radon and lung cancer risk.

PMID:20429156 NO_EVIDENCE

"Environmental factors in cancer... radon."

The provided literature does not contain any detailed content to evaluate the support of the statement.

+ 1 more reference

Mechanism Target:

PREDISPOSES Oncogenic Driver Mutations — Inhaled radon progeny irradiate bronchial epithelium with alpha particles, but the cited evidence is deliberately hedged and is qualified to current smokers at high residential concentrations, with the risk in never-smokers left unresolved. Recorded as a susceptibility contribution rather than an established mutational route.

Show evidence (1 reference)

PMID:12075673 SUPPORT Human Clinical

States there is some evidence that radon may contribute to lung cancer risk in current smokers at high residential concentrations, while noting the risk in non-smokers is unclear.

Household Smoky Coal Combustion

Domestic (indoor, unvented) burning of "smoky" bituminous coal for cooking and heating, the exposure behind the lung cancer incidence in Xuanwei County, Yunnan, China — the highest in the country and largely in never-smoking women. It is curated as a distinct exposure rather than as a variant of tobacco or generic air pollution because the comparison that isolates it is within-population: lifelong users of smoky (bituminous) coal versus lifelong users of smokeless (anthracite) coal in the same county, which controls for tobacco, geography, and diet.

Show evidence (3 references)

PMID:22936785 SUPPORT Human Clinical

"In Xuanwei, the domestic use of smoky coal is associated with a substantial increase in the absolute lifetime risk of developing lung cancer and is likely to represent one of the strongest effects of environmental pollution reported for cancer risk."

Retrospective cohort of 27,310 lifelong smoky-coal users versus 9,962 lifelong smokeless-coal users establishes the exposure as a lung cancer risk factor with the smoky-versus-smokeless contrast controlling for the shared local environment.

PMID:22936785 SUPPORT Human Clinical

"The absolute risks of lung cancer death before 70 years of age for men and women using smoky coal were 18% and 20%, respectively, compared with less than 0.5% among smokeless coal users of both sexes."

Quantifies the effect size, and shows it is not sex-restricted despite the genomic cohorts being drawn predominantly from never-smoking women.

PMID:26288819 SUPPORT Human Clinical

"In Xuanwei City of Yunnan Province, the lung cancer incidence is among the highest in China attributed to severe air pollution generated by combustion of smoky coal"

Independent statement attributing the regional incidence to smoky-coal combustion, from a genomics rather than an epidemiology group.

Mechanism Target:

TRIGGERS Oncogenic Driver Mutations — Coal-smoke polycyclic aromatic hydrocarbons — principally benzo[a]pyrene and methylated PAHs such as 5-methylchrysene — are the exposures that best explain risk in this population, and the resulting tumours carry a correspondingly distinct mutational spectrum: excess C:G to A:T transversions, a markedly higher mutated-gene count than tumours from control regions, and a BaP-attributed EGFR-G719X hotspot. The edge is typed INDIRECT_KNOWN_INTERMEDIATES rather than DIRECT because the intervening steps (PAH metabolic activation, bulky DNA adduct formation, error-prone bypass) are established chemistry that this entry does not model as its own nodes; the Xuanwei-specific attribution itself rests on mutational-signature inference, not on experimental demonstration in these patients.

Show evidence (3 references)

PMID:26288819 SUPPORT Human Clinical

"Whole genome sequencing revealed a mean of 289 somatic exonic mutations per tumor and the frequent C:G → A:T nucleotide substitutions in Xuanwei NSCLCs."

Sequencing of 164 NSCLCs from Xuanwei versus control regions where smoky coal was not used shows the exposure leaves a distinct somatic mutation spectrum, which is the mutational route from this exposure to the driver lesions modelled on the target node.

PMID:39432560 SUPPORT Human Clinical

"The BaP-induced mutation hotspot, EGFR-G719X, was present in 20% of XWLC which endowed XWLC with elevated MAPK pathway activations and worse outcomes compared to common EGFR mutations."

Ties the exposure to a specific driver allele and to the MAPK cascade already curated on the Oncogenic Driver Mutations node, in a cohort of 169 female never-smokers where coal smoke is the dominant exposure.

PMID:36921559 SUPPORT Human Clinical

"We confirmed the link between PAH exposures and lung cancer in smoky coal users and found exposures before age 18 to be especially important."

Identifies PAHs as the carcinogenic constituent of the exposure, which is what makes the mutational-signature attribution in the two genomic studies mechanistically coherent rather than merely correlative.

🔬

Biochemical Markers

Carcinoembryonic Antigen (Elevated)

Show evidence (1 reference)

PMID:37390106 SUPPORT

"Carcinoembryonic antigen (CEA) is the most frequently used tumor marker for non-small cell lung cancer (NSCLC)."

The reference discusses the use of CEA as a tumor marker in NSCLC, indicating its relevance and occasional elevated presence.

Cytokeratin Fragment 21-1 (Elevated)

Show evidence (1 reference)

PMID:8709175 SUPPORT

"The mean (SD) value of serum CYFRA 21-1 in NSCLC (13.26 (16.54)) was significantly higher than in benign lung diseases (1.74 (1.55)) (p < 0.0001)."

CYFRA 21-1 levels are elevated in NSCLC patients, supporting the statement of its occasional presence in a biochemical context.

📈

Progression

Onset

Age: 60-80

Show evidence (7 references)

PMID:15477641 NO_EVIDENCE

"What is clear is that currently over 50% of all patients with non-small cell lung cancer (NSCLC) are 65 years of age or older."

The study mentions the prevalence of NSCLC in patients aged 65 and older, but it does not directly address disease progression specifically in the 60-80 age range at the onset phase.

PMID:20471184 NO_EVIDENCE

"To assess rate of disease progression from diagnosis to initiation of treatment for Stage I-IIIB non-small-cell lung cancer (NSCLC)."

This study addresses the rate of disease progression from diagnosis to treatment initiation rather than focusing on age-specific progression at onset.

PMID:38377969 NO_EVIDENCE

"The objective of this study was to model multiple sclerosis (MS) disease progression and compare disease trajectories by sex, age of onset, and year of diagnosis."

The study focuses on multiple sclerosis and not on non-small cell lung cancer.

+ 4 more references

🪜

Stages

Localized

Stage I-III disease confined to the lung and regional lymph nodes, where multimodality treatment with curative intent (surgery, radiotherapy, chemotherapy, adjuvant targeted or immune therapy) is possible.

Metastatic

Advanced NSCLC with dissemination to distant organs, particularly brain, bone, liver, adrenal gland, and pleura. Metastatic behavior is shaped by oncogenic receptor tyrosine kinase signaling, epithelial plasticity, angiogenesis, immune checkpoint engagement, and organ-specific interactions within the brain and bone microenvironments.

Folded in from the former Metastatic_NSCLC entry (cancer granularity ladder, design decisions §3a). Metastatic NSCLC couples oncogenic kinase addiction with immune checkpoint adaptation and strong organotropism to brain and bone; the EMT and Invasion and Brain Metastasis Seed-and-Soil Biology pathophysiology nodes carry the stage-specific mechanism content.

Show evidence (1 reference)

PMID:31343665 SUPPORT Human Clinical

"Overall survival curves showed estimated 5-year rates of 34.2% among patients with melanoma, 27.7% among patients with RCC, and 15.6% among patients with NSCLC."

Provides a 5-year survival benchmark for the metastatic stage of NSCLC.

📊

Related Datasets

Single cell RNA sequencing of lung adenocarcinoma geo:GSE131907

Large-scale single-cell RNA sequencing from 11 adjacent normal and 15 tumor tissue samples from NSCLC patients (stages I-IV). After quality filtering, 98,504 cells retained including 16,046 epithelial, 5,468 stromal, and 76,990 immune cells.

human SINGLE CELL RNA SEQ n=26

lung tumor tissue UBERON:0002048

Conditions: NSCLC tumor tissue adjacent normal lung tissue

Comprehensive single-cell atlas identifying eight major cell types. Resolves tumor-infiltrating immune cell heterogeneity relevant to immunotherapy response. Part of integrated NSCLC scRNA-seq resource.

Comprehensive transcriptomic profiles of non-small cell lung cancer by single-cell RNA-seq geo:GSE119911

Single-cell RNA sequencing profiling over 9,000 individual cells from tumor and adjacent normal tissues of 20 patients with stage I-IV NSCLC using modified STRT-seq technique.

human SINGLE CELL RNA SEQ n=106

lung tumor tissue UBERON:0002048

Conditions: NSCLC tumor tissue adjacent normal tissue

Characterizes inter-patient and intra-tumor heterogeneity including epithelial, stromal, and immune cell compartments. Useful for understanding cancer progression and therapeutic strategies

The single-cell lung cancer atlas (LuCA) -- extended atlas cellxgene:edb893ee-4066-4128-9aec-5eb2b03f8287

Comprehensive single-cell lung cancer atlas integrating data across multiple NSCLC subtypes and stages. Provides detailed characterization of tumor microenvironment cell populations including cancer cells, immune cells, and stromal compartments.

human SINGLE CELL RNA SEQ

lung tumor tissue UBERON:0002048

Conditions: lung adenocarcinoma non-small cell lung carcinoma normal

PMID:36368568

CZI CELLxGENE collection. Extended LuCA atlas for tumor microenvironment analysis and virtual cell modeling.

Efficacy and safety of entrectinib in patients with ROS1-positive advanced/metastatic non-small cell lung cancer (NSCLC) from the Blood First Assay Screening Trial (BFAST) ega:EGAS50000000105

BFAST is a global, open-label, multicohort trial that evaluates the efficacy and safety of multiple therapies in patients with advanced/metastatic NSCLC and targetable alterations, identified by blood-based molecular testing. We present data from Cohort D (ROS1-positive). Patients ≥18 years old with stage IIIB/IV, ROS1-positive NSCLC detected by blood-based testing, received entrectinib 600 mg daily. At data cut-off (November 2021), 55 patients were enrolled and 54 had measurable disease.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Metastatic Non-Small Cell Lung Cancer"); description-level mentions were not accepted. EGA study_type: Cancer Genomics. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Multi-omic analyses from a randomized phase II study of epigenetic priming followed by nivolumab in previously treated metastatic non-small cell lung cancer ega:EGAS50000000913

Emergence of resistance to immune checkpoint blockade (ICB) mandates the development of strategies for ICB sensitization. We aimed to understand the effects of epigenetic priming in re-shaping the tumor microenvironment, together with molecular drivers of therapeutic response of epigenetic therapy followed by ICB in non-small cell lung cancer (NSCLC; NCT01928576). This was done through a multi-omic approach encompassing both genomic and transcriptomic analyses. Findings suggest that epigenetic therapy may reshape the tumor microenvironment towards a more inflamed phenotype and prime responses to immunotherapy.

human

🧫

Experimental Models

Human orthotopic NSCLC lung organ-on-chip (Wyss Institute) ORGAN_ON_CHIP namo:OrganOnChip

Microfluidic human lung organ chip in which non-small-cell lung cancer cells are grown within a reconstituted human lung microenvironment under cyclic mechanical actuation that mimics breathing motions. A non-animal New Approach Methodology that reproduces organ-microenvironment-specific tumour growth, tumour dormancy and tyrosine kinase inhibitor responses in vitro, and that resolves the influence of physical breathing cues on EGFR and MET signalling.

Organism

human NCBITaxon:9606

Tissue

lung UBERON:0002048

Cell source

Human non-small-cell lung cancer cells co-cultured with human lung epithelium in a reconstituted orthotopic lung microenvironment

Culture

Two-channel microfluidic lung organ chip under continuous perfusion with cyclic mechanical actuation reproducing breathing-associated strain

Publication

PMID:29020635

Pathograph links

Oncogenic Driver Mutations measures fidelity: moderate The chip reads out driver-kinase-dependent therapeutic response, reproducing the tyrosine kinase inhibitor sensitivity seen in patients and resolving EGFR- and MET-mediated modulation of that response by the mechanical microenvironment.

Limitations: Only EGFR and MET signalling were implicated; the ALK and ROS1 rearrangement arms of this node were not modelled. The published abstract reports lung cancer cell lines in a reconstituted microenvironment rather than patient-derived tumour carrying its native driver spectrum, so allele-level genotype-response relationships are not established by this system.

Readouts

Tyrosine kinase inhibitor therapeutic response

EGFR and MET receptor tyrosine kinase signaling underlying TKI response GO:0007169

Direction: ALTERED

Interpretation: TKI response in the chip tracked the responses observed in patients, and was itself shifted by breathing-like mechanical cues acting through EGFR and MET.

Show evidence (1 reference)

PMID:29020635 SUPPORT In Vitro

"revealed a previously unknown sensitivity of lung cancer cell growth, invasion, and TKI therapeutic responses to physical cues associated with breathing motions, which appear to be mediated by changes in signaling through epidermal growth factor receptor (EGFR) and MET protein kinase"

Reports that the chip measured TKI therapeutic response and attributed its mechanical modulation to EGFR and MET signalling.

Show evidence (1 reference)

PMID:29020635 SUPPORT In Vitro

"recapitulate organ microenvironment-specific cancer growth, tumor dormancy, and responses to tyrosine kinase inhibitor (TKI) therapy observed in human patients in vivo"

Supports treating the chip as informative for driver-kinase-directed therapeutic response, since it reproduces the TKI responses observed in patients.

Tumor Microenvironment Remodeling partially recapitulates fidelity: moderate The chip reconstitutes an orthotopic lung microenvironment in which tumour growth and dormancy are microenvironment-specific, and adds the mechanical dimension of breathing motion that static culture cannot supply.

Limitations: The microenvironment modelled is epithelial and mechanical. The abstract reports no immune, myeloid or fibroblast compartment, so the immune-remodelling and desmoplastic facets of this node are outside what the system captures.

Readouts

Microenvironment-specific tumour growth and dormancy

Direction: ALTERED

Interpretation: Growth and entry into dormancy depended on the reconstituted organ microenvironment and on breathing-associated mechanical cues.

Show evidence (1 reference)

PMID:29020635 SUPPORT In Vitro

"providing an experimental model to study cancer persister cells and mechanisms of tumor dormancy in vitro"

Establishes tumour dormancy and persister-cell behaviour as measurable outputs of the reconstituted microenvironment.

Show evidence (1 reference)

PMID:29020635 SUPPORT In Vitro

"recapitulate organ microenvironment-specific cancer growth, tumor dormancy, and responses to tyrosine kinase inhibitor (TKI) therapy observed in human patients in vivo"

Supports the claim that tumour behaviour in this system is set by the reconstituted organ microenvironment rather than by the tumour cells alone.

Metastasis partially recapitulates fidelity: low Local invasion of lung cancer cells is measurable in the chip and is sensitive to breathing-associated mechanical cues.

Limitations: Only the local invasive step is represented. The system has no circulation, distant organ site, or colonisation compartment, so intravasation, survival in transit and metastatic outgrowth - the steps that make this node clinically decisive - are not modelled.

Readouts

Lung cancer cell invasion under cyclic mechanical strain

Direction: ALTERED

Interpretation: Invasion was shown to be mechanically sensitive, changing with breathing-like actuation rather than being a fixed property of the tumour cells.

Show evidence (1 reference)

PMID:29020635 SUPPORT In Vitro

Reports invasion as a measured outcome and identifies mechanical cues as a determinant of it.

Show evidence (1 reference)

PMID:29020635 SUPPORT In Vitro

"revealed a previously unknown sensitivity of lung cancer cell growth, invasion, and TKI therapeutic responses to physical cues associated with breathing motions"

Names invasion as one of the behaviours the chip resolves, which is the local invasive step of this node and the only facet of it the system informs.

Curated from the NAMeRS 2026 symposium New Approach Methodology tracker (monarch-initiative/dismech#4873), Panel 1 organ-chip case study. The underlying evidence item was already cited on the Targeted Therapy treatment; this section adds the structured model record and its pathograph links.

{ }

Source YAML

click to show

name: Non-Small Cell Lung Cancer
creation_date: '2025-12-04T16:57:31Z'
synonyms:
- NSCLC
description: >-
  Non-small cell lung cancer is driven by oncogenic driver mutations in genes such as EGFR, ALK, ROS1, and BRAF that produce constitutive proliferative signaling.
  Tumors evade immune destruction, remodel an immunosuppressive microenvironment, rewire metabolism, and induce angiogenesis to sustain growth.
  These capabilities enable local invasion and metastatic spread, commonly to the brain, bone, liver, and adrenal glands.
categories:
- Lung Cancer
- Respiratory Malignancy
has_subtypes:
- name: Adenosquamous Carcinoma
  description: A rare subtype displaying both adenocarcinoma and squamous cell carcinoma features.
  evidence:
  - reference: PMID:37681230
    reference_title: "Clinicopathologic study of stage I adenosquamous carcinoma of the lung."
    supports: SUPPORT
    snippet: Adenosquamous carcinoma of the lung is a characteristic tumor that has both adenocarcinoma and squamous cell carcinoma components.
    explanation: This excerpt confirms that adenosquamous carcinoma displays features of both adenocarcinoma and squamous cell carcinoma.
  - reference: PMID:20004040
    reference_title: "Are adenosquamous lung carcinomas a simple mix of adenocarcinomas and squamous cell carcinomas, or more complex at the molecular level?"
    supports: SUPPORT
    snippet: Adenocarcinomas (AC), squamous cell carcinomas (SCC) and adenosquamous carcinomas (ASC) are three histological subtypes of non-small-cell lung carcinomas (NSCLC). ASC are morphologically mixed tumours that contain the two cell components AC and SCC.
    explanation: This literature supports the statement by explaining that adenosquamous carcinoma (ASC) contains both adenocarcinoma (AC) and squamous cell carcinoma (SCC) components.
- name: ALK-rearranged NSCLC
  description: NSCLC with ALK gene rearrangements, responsive to ALK inhibitors.
  evidence:
  - reference: PMID:27637426
    reference_title: "ALK alterations and inhibition in lung cancer."
    supports: SUPPORT
    snippet: An early result of this search was the discovery of NSCLC driven by activating rearrangements of the anaplastic lymphoma kinase (ALK) gene. In an astoundingly brief period following the recognition of ALK-positive NSCLC, details of the biology, clinicopathologic features, development of targeted inhibitors, mechanisms of therapeutic resistance, and new generations of treatment were elucidated.
    explanation: This reference supports that NSCLC with ALK gene rearrangements is a subtype that is responsive to ALK inhibitors.
  - reference: PMID:21233671
    reference_title: "What's new in non-small cell lung cancer for pathologists: the importance of accurate subtyping, EGFR mutations and ALK rearrangements."
    supports: SUPPORT
    snippet: The significance of EGFR and ALK mutations in NSCLC and the impact of these genotypes on pathology and clinical practice are also reviewed.
    explanation: This article mentions the impact of ALK mutations and the necessity to identify NSCLCs harboring these mutations due to their sensitivity to specific agents like ALK inhibitors.
  - reference: PMID:24998601
    reference_title: "Looking for a new panacea in ALK-rearranged NSCLC: may be Ceritinib?"
    supports: SUPPORT
    snippet: The accelerated approval of the first ALK-inhibitor, Crizotinib and more recently Ceritinib, without a Phase III randomized, clinical trial, has been an amazing success story in lung cancer research, marking the beginning of a new decade of targeted drugs development.
    explanation: This reference discusses the success and approval of ALK inhibitors like Crizotinib and Ceritinib for the treatment of ALK-rearranged NSCLC, supporting the claim.
  - reference: PMID:31720561
    reference_title: "Targeted therapies for ROS1-rearranged non-small cell lung cancer."
    supports: SUPPORT
    snippet: Similarly to anaplastic lymphoma kinase (ALK)-positive NSCLC, patients with ROS1+ NSCLC tend to have minimal smoking and be of the female sex. In most cases, adenocarcinoma is the dominant histology.
    explanation: This indirectly supports that ALK-rearranged NSCLC is a recognized subtype as it compares ROS1+ NSCLC to ALK-positive NSCLC in terms of patient characteristics and histology.
  - reference: PMID:33387080
    reference_title: "Upfront Management of ALK-Rearranged Metastatic Non-small Cell Lung Cancer: One Inhibitor Fits All?"
    supports: SUPPORT
    snippet: Anaplastic lymphoma kinase (ALK) rearrangements represent a seldom event in non-small cell lung cancer (NSCLC). Given the oncogene alteration, ALK targeting represents the main therapeutic strategy.
    explanation: This recent review discusses the targeting of ALK rearrangements as a therapeutic strategy, supporting that ALK-rearranged NSCLC is a recognized subtype responsive to ALK inhibitors.
- name: EGFR-mutant NSCLC
  description: NSCLC with activating EGFR mutations, responsive to EGFR inhibitors.
  evidence:
  - reference: PMID:28017789
    reference_title: "Driven by Mutations: The Predictive Value of Mutation Subtype in EGFR-Mutated Non-Small Cell Lung Cancer."
    supports: SUPPORT
    snippet: Although the most common EGFR mutations-exon 19 deletions or L858R mutations-predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs)...
    explanation: This excerpt confirms that NSCLC with activating EGFR mutations (such as exon 19 deletions or L858R mutations) are responsive to EGFR TKIs.
  - reference: PMID:15946581
    reference_title: "Epidermal growth factor receptor inhibitors and their role in non-small-cell lung cancer."
    supports: SUPPORT
    snippet: A genetic mutation in EGFR has also been correlated with an increase in response.
    explanation: This statement supports the idea that NSCLC with EGFR mutations are responsive to EGFR inhibitors.
  - reference: PMID:35993098
    reference_title: "EGFR-mutant NSCLC: monitoring the molecular evolution of tumors in 2022."
    supports: SUPPORT
    snippet: Osimertinib is the current standard-of-care for the first-line treatment of EGFR-mutant NSCLC.
    explanation: Osimertinib, an EGFR inhibitor, being the standard-of-care for EGFR-mutant NSCLC indicates that this subtype is responsive to EGFR inhibitors.
  - reference: PMID:24857124
    reference_title: "Management and future directions in non-small cell lung cancer with known activating mutations."
    supports: SUPPORT
    snippet: Somatic TKI-sensitizing EGFR mutations (such as exon 19 deletions and L858R substitutions) are the most robust predictive biomarker for symptom improvement, radiographic response, and increment in progression-free survival (PFS) when EGFR TKIs (gefitinib, erlotinib, and afatinib) are used for patients with advanced NSCLC.
    explanation: This excerpt specifically notes the responsiveness of NSCLC with TKI-sensitizing EGFR mutations to EGFR inhibitors.
  - reference: PMID:25145405
    reference_title: "Drug resistance to EGFR tyrosine kinase inhibitors for non-small cell lung cancer."
    supports: SUPPORT
    snippet: Several large Phase III trials have shown that EGFR-TKIs improved the progression-free survival of patients with EGFR mutant NSCLC compared to conventional chemotherapy.
    explanation: This indicates the effectiveness of EGFR inhibitors in treating EGFR-mutant NSCLC.
progression:
- phase: Onset
  age_range: 60-80
  evidence:
  - reference: PMID:15477641
    reference_title: "Non-small cell lung cancer in the elderly."
    supports: NO_EVIDENCE
    snippet: What is clear is that currently over 50% of all patients with non-small cell lung cancer (NSCLC) are 65 years of age or older.
    explanation: The study mentions the prevalence of NSCLC in patients aged 65 and older, but it does not directly address disease progression specifically in the 60-80 age range at the onset phase.
  - reference: PMID:20471184
    reference_title: "Rapid disease progression with delay in treatment of non-small-cell lung cancer."
    supports: NO_EVIDENCE
    snippet: To assess rate of disease progression from diagnosis to initiation of treatment for Stage I-IIIB non-small-cell lung cancer (NSCLC).
    explanation: This study addresses the rate of disease progression from diagnosis to treatment initiation rather than focusing on age-specific progression at onset.
  - reference: PMID:38377969
    reference_title: "Modelling Disease Progression of Multiple Sclerosis in a South Wales Cohort."
    supports: NO_EVIDENCE
    snippet: The objective of this study was to model multiple sclerosis (MS) disease progression and compare disease trajectories by sex, age of onset, and year of diagnosis.
    explanation: The study focuses on multiple sclerosis and not on non-small cell lung cancer.
  - reference: PMID:37681230
    reference_title: "Clinicopathologic study of stage I adenosquamous carcinoma of the lung."
    supports: NO_EVIDENCE
    snippet: Adenosquamous carcinoma of the lung is a characteristic tumor that has both adenocarcinoma and squamous cell carcinoma components.
    explanation: This study focuses on adenosquamous carcinoma and does not address age-specific progression of NSCLC in the 60-80 age range specifically at onset.
  - reference: PMID:34911717
    reference_title: "Colorectal cancer in adolescents and young adults with Lynch syndrome: a Danish register-based study."
    supports: NO_EVIDENCE
    snippet: To assess clinicopathological predictors and prognosis in early-onset colorectal cancer (CRC) in Lynch syndrome with comparison to patients diagnosed from age 40 and up.
    explanation: The study is about early-onset colorectal cancer in patients with Lynch syndrome and is not related to NSCLC.
  - reference: PMID:26729443
    reference_title: "MET Exon 14 Mutations in Non-Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression."
    supports: NO_EVIDENCE
    snippet: Non-small-cell lung cancers (NSCLCs) harboring mutations in MET exon 14 and its flanking introns may respond to c-Met inhibitors.
    explanation: While the study addresses genomic characteristics and treatment responses for NSCLC with MET exon 14 mutations, it does not specifically discuss disease progression at onset in the 60-80 age range.
  - reference: PMID:29432718
    reference_title: "Natural History of Ground-Glass Lesions Among Patients With Previous Lung Cancer."
    supports: NO_EVIDENCE
    snippet: Among patients with previous lung cancer, the malignant potential of subsequent ground-glass opacities (GGOs) on computed tomography remains unknown.
    explanation: The study examines ground-glass opacities among patients with a history of lung cancer, not specifically the progression of NSCLC in the 60-80 age range at onset.
stages:
- name: Localized
  description: >-
    Stage I-III disease confined to the lung and regional lymph nodes, where
    multimodality treatment with curative intent (surgery, radiotherapy,
    chemotherapy, adjuvant targeted or immune therapy) is possible.
- name: Metastatic
  description: >-
    Advanced NSCLC with dissemination to distant organs, particularly brain,
    bone, liver, adrenal gland, and pleura. Metastatic behavior is shaped by
    oncogenic receptor tyrosine kinase signaling, epithelial plasticity,
    angiogenesis, immune checkpoint engagement, and organ-specific
    interactions within the brain and bone microenvironments.
  notes: >-
    Folded in from the former Metastatic_NSCLC entry (cancer granularity
    ladder, design decisions §3a). Metastatic NSCLC couples oncogenic kinase
    addiction with immune checkpoint adaptation and strong organotropism to
    brain and bone; the EMT and Invasion and Brain Metastasis Seed-and-Soil
    Biology pathophysiology nodes carry the stage-specific mechanism content.
  evidence:
  - reference: PMID:31343665
    reference_title: "Five-Year Survival and Correlates Among Patients With Advanced Melanoma, Renal Cell Carcinoma, or Non-Small Cell Lung Cancer Treated With Nivolumab."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Overall survival curves showed estimated 5-year rates of 34.2% among patients with melanoma, 27.7% among patients with RCC, and 15.6% among patients with NSCLC.
    explanation: Provides a 5-year survival benchmark for the metastatic stage of NSCLC.
pathophysiology:
- name: Oncogenic Driver Mutations
  conforms_to: "sustaining_proliferative_signaling#Oncogenic Growth-Signal Lesion"
  description: Mutations in genes like EGFR, ALK, ROS1, and BRAF lead to uncontrolled cell growth and survival.
  biological_processes:
  - preferred_term: transmembrane receptor protein tyrosine kinase signaling pathway
    description: Dysregulated RTK signaling via EGFR, ALK, MET drives proliferation and survival
    term:
      id: GO:0007169
      label: cell surface receptor protein tyrosine kinase signaling pathway
  - preferred_term: MAPK cascade
    description: Constitutive MAPK activation via KRAS, EGFR, ALK mutations
    term:
      id: GO:0000165
      label: MAPK cascade
  evidence:
  - reference: PMID:22987962
    reference_title: "Going beyond EGFR."
    supports: SUPPORT
    snippet: Mutations in EGFR best illustrate the therapeutic relevance of molecular classification. This article reviews the scope of presently known driving molecular alterations, including ROS1, BRAF, KRAS, HER2 and PIK3CA, with a special emphasis on aLK rearrangements, and outlines their potential therapeutic applications.
    explanation: This reference confirms that mutations in genes such as EGFR, ALK, ROS1, and BRAF are recognized as driving molecular alterations that underpin the malignant phenotype of non-small cell lung cancer.
  - reference: PMID:29989448
    reference_title: "Oncogene addicted non-small-cell lung cancer: current standard and hot topics."
    supports: SUPPORT
    snippet: Activating mutations in the EGFR and rearrangements in the anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) genes have been identified as oncogenic drivers in non-small-cell lung cancer.
    explanation: The reference supports that mutations in EGFR, ALK, and ROS1 genes serve as oncogenic drivers in non-small cell lung cancer, contributing to uncontrolled cell growth and survival.
  - reference: PMID:35709927
    reference_title: "Genetic determinants of lung cancer: Understanding the oncogenic potential of somatic missense mutations."
    supports: SUPPORT
    snippet: The aim of the current study is to extract meaningful information from the online somatic mutation data (retrieved from cBioPortal) of 16 most significantly mutated oncogenes in non-small-cell lung cancer (NSCLC), namely EGFR, NRAS, KRAS, HER2 (ERBB2), RET, MET, ROS1, FGFR1, BRAF ... for improving our understanding of the pathobiology of the lung cancer.
    explanation: This reference further lists EGFR, ALK, ROS1, and BRAF among the significantly mutated oncogenes in non-small cell lung cancer, thus supporting the statement.
  - reference: PMID:31627700
    reference_title: "Uncommon EGFR Mutations in Non-Small Cell Lung Cancer and Their Impact on the Treatment."
    supports: SUPPORT
    snippet: Epidermal growth factor receptor (EGFR) mutations play an important role in the pathogenesis of non-small cell lung cancer. ... In patients with EGFR mutations, a significant improvement in therapeutic outcomes was achieved with the administration of targeted therapy using tyrosine kinase inhibitors.
    explanation: This reference confirms the crucial role of EGFR mutations in NSCLC pathogenesis, indicating their role in driving tumor growth and survival.
  - reference: PMID:33435440
    reference_title: "Molecular Epidemiology of the Main Druggable Genetic Alterations in Non-Small Cell Lung Cancer."
    supports: SUPPORT
    snippet: Testing the presence of driver mutations in specific genes in lung tumors has thus radically changed the clinical management and outcomes of the disease. ... namely EGFR, KRAS, BRAF, MET, and HER2 mutations or amplification, as well as ALK and ROS1 fusions.
    explanation: This reference supports that identifying driver mutations in genes like EGFR, ALK, ROS1, and BRAF is crucial in the clinical management of NSCLC, implying their role in uncontrolled cell growth and survival.
- name: Immune Evasion
  description: Cancer cells develop mechanisms to evade detection and destruction by the immune system.
  biological_processes:
  - preferred_term: epithelial to mesenchymal transition
    description: EMT programs linked to immune suppression and therapy resistance; EGFR-mutant tumors may transform to SCLC
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
  - preferred_term: negative regulation of immune response
    modifier: INCREASED
    term:
      id: GO:0050777
      label: negative regulation of immune response
  evidence:
  - reference: PMID:27416962
    reference_title: "Mechanisms of immune evasion and current status of checkpoint inhibitors in non-small cell lung cancer."
    supports: SUPPORT
    snippet: We are also beginning to understand the methods of immune evasion employed by NSCLC which likely contribute to the 20% response rate to immunotherapy.
    explanation: The study indicates that non-small cell lung cancer (NSCLC) employs methods of immune evasion, which aligns with the statement.
  - reference: PMID:29107330
    reference_title: "Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution."
    supports: SUPPORT
    snippet: Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. ... Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity.
    explanation: The study describes immune evasion mechanisms such as HLA loss in NSCLC, supporting the statement.
  - reference: PMID:37130455
    reference_title: "Tumor immune evasion through loss of MHC class-I antigen presentation."
    supports: SUPPORT
    snippet: Since MHC-I antigen presentation is not essential for cell growth or survival, many cancers inactivate this pathway, and thereby escape control by CD8 T cells. Such immune evasion allows cancers to progress and also become resistant to CD8 T-cell-based immunotherapies, such as checkpoint blockade.
    explanation: The study discusses how NSCLC cells evade the immune system by inactivating MHC-I antigen presentation, supporting the statement.
  - reference: PMID:34484217
    reference_title: "In Situ Overexpression of Matricellular Mechanical Proteins Demands Functional Immune Signature and Mitigates Non-Small Cell Lung Cancer Progression."
    supports: SUPPORT
    snippet: These data raise the possibility that proteins with mechanical barrier function in NSCLC may be used by cancer cells to protect them from immune cell infiltration and immune-mediated destruction, which can otherwise be targeted effectively with immunotherapy or collagen therapy.
    explanation: The study mentions mechanisms employed by NSCLC cells to evade immune destruction, supporting the statement.
  - reference: PMID:37086716
    reference_title: "Early immune pressure initiated by tissue-resident memory T cells sculpts tumor evolution in non-small cell lung cancer."
    supports: SUPPORT
    snippet: These data demonstrate that enhanced TRM-like activity prior to tumor development shapes the evolution of tumor immunogenicity and can impact immunotherapy outcomes.
    explanation: The study outlines mechanisms of immune evasion in NSCLC, such as the loss of MHC class I protein expression, supporting the statement.
  - reference: PMID:31627272
    reference_title: "Programmed Death Ligand 1 Indicates Pre-Existing Adaptive Immune Response by Tumor-Infiltrating CD8(+) T Cells in Non-Small Cell Lung Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Aberrant expression of programmed death ligand 1 (PD-L1) on tumor cells impedes antitumor immunity and instigates immune evasion.
    explanation: PD-L1-mediated adaptive immune resistance is a specific immune-evasion mechanism in NSCLC; folded in from the former Metastatic_NSCLC entry.
- name: Angiogenesis
  conforms_to: "tumor_angiogenesis#Angiogenic Switch and VEGF-Driven Neovascularization"
  description: Tumors induce the formation of new blood vessels to support their growth and metastasis.
  evidence:
  - reference: PMID:12824870
    reference_title: "Molecular mechanisms of angiogenesis in non-small cell lung cancer, and therapeutics targeting related molecules."
    supports: SUPPORT
    snippet: Angiogenesis, neovascularization from pre-existing vasculature, is necessary to supply oxygen and nutrition for tumor growth in both primary and distant organs.
    explanation: This reference discusses the requirement of angiogenesis in the growth and metastasis of non-small cell lung cancer (NSCLC).
  - reference: PMID:36269457
    reference_title: "Management and Treatment of Non-small Cell Lung Cancer with MET Alteration and Mechanisms of Resistance."
    supports: SUPPORT
    snippet: Pathologic activation of MET can be achieved with increased number of gene copies overexpression, or decreased protein degradation through several mechanisms, including mutations, amplifications, or fusions... Besides its role as primary driver, MET activation might also mediate resistance to kinase inhibitors in NSCLC with various other actionable alterations.
    explanation: While the primary focus is not on angiogenesis, it mentions mechanisms of tumor growth and resistance, which can be linked to angiogenesis indirectly.
  - reference: PMID:26222080
    reference_title: "The Biology of Brain Metastasis: Challenges for Therapy."
    supports: SUPPORT
    snippet: Many patients with lung cancer, breast cancer, and melanoma develop brain metastases that are resistant to conventional therapy. The median survival for untreated patients is 1 to 2 months, which may be extended to 6 months with surgery, radiotherapy, and chemotherapy.
    explanation: This reference indirectly supports the statement by talking about brain metastasis and tumor progression but does not specifically focus on angiogenesis.
  - reference: PMID:22550239
    reference_title: "Field cancerization in non-small cell lung cancer: implications in disease pathogenesis."
    supports: NO_EVIDENCE
    snippet: Lung cancer, of which non-small cell lung cancer (NSCLC) composes the majority, is the leading cause of cancer-related deaths in the United States and worldwide... field cancerization phenomenon...
    explanation: The reference discusses field cancerization and the complexities of NSCLC but does not provide specific evidence related to angiogenesis.
- name: Tumor Microenvironment Remodeling
  description: Macrophage-dominant immunosuppressive niches with reduced NK and T cell cytotoxicity; tumor-associated macrophages adopt cholesterol export and iron efflux programs that suppress anti-tumor immunity.
  notes: Single-cell spatial mapping reveals inverse relationship between anti-inflammatory macrophages and NK/T cells
  cell_types:
  - preferred_term: macrophage
    description: Tumor-associated macrophages (TAMs) reprogrammed to cholesterol export and iron efflux states; dominant immunosuppressive population
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: T cell
    description: Reduced T cell infiltration and cytotoxicity in immunosuppressive niches; altered checkpoint co-expression patterns
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: natural killer cell
    description: Reduced NK cell cytotoxicity; inverse relationship with anti-inflammatory macrophages
    term:
      id: CL:0000623
      label: natural killer cell
  - preferred_term: fibroblast
    description: Cancer-associated fibroblasts (CAFs) contribute to immunosuppressive niches and stromal remodeling
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: regulation of T cell activation
    description: Altered T cell activation in TME; checkpoint co-expression patterns; dual ICI modulates CD4+ responses
    term:
      id: GO:0050863
      label: regulation of T cell activation
  locations:
  - preferred_term: parenchyma of lung
    description: Primary site of TME remodeling
    term:
      id: UBERON:0008946
      label: lung parenchyma
- name: Metabolic Rewiring
  conforms_to: "deregulated_cellular_energetics#Biosynthetic Diversion for Biomass Production"
  description: KRAS/LKB1 co-mutant tumors depend on oxidative pentose phosphate pathway (PPP) via G6PD for NADPH production, redox balance, and lipogenesis; G6PD ablation selectively suppresses tumor growth and activates p53.
  notes: Represents a therapeutically exploitable metabolic vulnerability in KRAS/LKB1 tumors
  biological_processes:
  - preferred_term: pentose-phosphate shunt
    description: KRAS/LKB1 tumors depend on oxidative PPP via G6PD for NADPH and lipogenesis
    term:
      id: GO:0006098
      label: pentose-phosphate shunt
  - preferred_term: cellular response to oxidative stress
    description: G6PD impairment disrupts redox balance and activates p53
    term:
      id: GO:0034599
      label: cellular response to oxidative stress
- name: MTAP Deficiency-Driven Collective Cell Migration
  description: >-
    MTAP deletion leads to intracellular MTA accumulation, which suppresses PRMT5 activity and reduces global protein symmetric dimethylarginine (sDMA) modification.
    Decreased sDMA enhances USF2 phosphorylation and facilitates USF2 nuclear translocation and binding to the WNT3A promoter,
    while simultaneously reducing DNA CpG methylation of the WNT3A promoter, synergistically activating WNT3A transcription.
    Upregulated WNT3A strengthens intercellular crosstalk between leader and follower cells and drives cytoskeletal remodeling in leader cells,
    thereby accelerating collective cell migration and metastatic progression. This mechanism represents a subtype-specific vulnerability in MTAP-deficient NSCLC.
  notes: MTAP-deficient NSCLC exhibits significantly shorter overall survival; collective cell migration is the primary phenotypic output; WNT3A inhibitor C59 effectively blocks both CCM formation and metastasis.
  cell_types:
  - preferred_term: neoplastic cell
    description: Malignant cells organized in leader-follower clusters undergoing collective cell migration
    term:
      id: CL:0001063
      label: neoplastic cell
  biological_processes:
  - preferred_term: protein methylation
    description: PRMT5 suppression by MTA accumulation; reduced symmetric dimethylarginine (sDMA) protein modifications
    term:
      id: GO:0006479
      label: protein methylation
    modifier: DECREASED
  - preferred_term: Wnt signaling pathway
    description: WNT3A transcriptional upregulation via USF2-mediated promoter activation and CpG demethylation
    term:
      id: GO:0016055
      label: Wnt signaling pathway
    modifier: INCREASED
  - preferred_term: cell migration
    description: Collective cell migration driven by WNT3A-mediated leader cell cytoskeletal rearrangement and increased intercellular crosstalk
    term:
      id: GO:0016477
      label: cell migration
    modifier: INCREASED
  - preferred_term: cell-cell adhesion
    description: Elevated adhesion among follower cells within collective migration clusters
    term:
      id: GO:0098609
      label: cell-cell adhesion
    modifier: INCREASED
  evidence:
  - reference: PMID:42432327
    reference_title: "MTAP deficiency enhances collective metastasis in non-small cell lung cancer via WNT3A methylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mechanistically, MTAP deletion leads to intracellular MTA accumulation, which suppresses PRMT5 activity and reduces global protein symmetric dimethylarginine (sDMA) modification. Decreased sDMA further enhances USF2 phosphorylation and nuclear translocation, facilitates USF2 binding to the WNT3A promoter, and concurrently reduces DNA CpG methylation of the WNT3A promoter, thereby synergistically activating WNT3A transcription."
    explanation: This reference directly describes the mechanistic cascade from MTAP deficiency through PRMT5-sDMA suppression and USF2-WNT3A activation that drives collective cell migration in MTAP-deficient NSCLC.
  - reference: PMID:42432327
    reference_title: "MTAP deficiency enhances collective metastasis in non-small cell lung cancer via WNT3A methylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Upregulated WNT3A strengthens intercellular crosstalk between leader and follower cells, elevates adhesion among follower cells, and drives cytoskeletal remodeling in leader cells, ultimately accelerating CCM progression."
    explanation: WNT3A upregulation drives collective cell migration through enhanced intercellular crosstalk and cytoskeletal remodeling.
  - reference: PMID:42432327
    reference_title: "MTAP deficiency enhances collective metastasis in non-small cell lung cancer via WNT3A methylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical sample analysis revealed that NSCLC patients with MTAP deficiency exhibited significantly shorter overall survival."
    explanation: MTAP deficiency is associated with poor prognosis in NSCLC patients.
  - reference: PMID:42432327
    reference_title: "MTAP deficiency enhances collective metastasis in non-small cell lung cancer via WNT3A methylation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the WNT3A specific inhibitor C59 effectively blocked CCM formation and mitigated collective metastasis in MTAP‑deficient NSCLC."
    explanation: WNT3A inhibition represents a therapeutic vulnerability in MTAP-deficient NSCLC, supporting WNT3A as a validated therapeutic target.
- name: Metastasis
  conforms_to: "invasion_and_metastasis#Metastatic Colonization"
  description: Cancer cells spread from the primary tumor site to distant organs, commonly to the brain, bones, liver, and adrenal glands.
  downstream:
  - target: Brain Metastasis Seed-and-Soil Biology
    description: >-
      Disseminated NSCLC cells that reach the cerebral circulation must additionally
      survive vascular arrest, cross the blood-brain barrier, and adapt to the neural
      microenvironment to establish brain metastases.
  evidence:
  - reference: PMID:33533174
    reference_title: "The landscape of small cell lung cancer metastases: Organ specificity and timing."
    supports: SUPPORT
    snippet: Our results are suggestive for particular site- and sequence-specific metastasis patterns in human SCLC. SCLC bone metastases tend to appear together with liver metastases, while brain metastases occur together with adrenal gland metastases.
    explanation: While this article primarily deals with small cell lung cancer (SCLC), it does mention metastasis pattern to common sites such as liver and adrenal glands, indicating support for the general concept of lung cancer metastasizing to these distant organs.
  - reference: PMID:31151683
    reference_title: "Surgical approach of non-small cell lung cancer with extrapulmonary metastasis."
    supports: SUPPORT
    snippet: Nearly 75% of patients have a disseminated carcinoma at diagnosis. Up to 50% of patients with a localized disease will develop metastasis. Nevertheless, the current scientific evidence has demonstrated that when the metastatic disease is limited, particularly in specific locations such as the brain and the adrenal glands, a multidisciplinary approach with radical intent could achieve a longer survival.
    explanation: This article supports the statement as it mentions that NSCLC can metastasize to the brain and adrenal glands.
  - reference: PMID:23322021
    reference_title: "CXCR4/CXCL12 in non-small-cell lung cancer metastasis to the brain."
    supports: SUPPORT
    snippet: At least one third of the people with lung cancer develop brain metastases at some point during their disease, even often before the diagnosis of lung cancer is made. The high rate of brain metastasis makes lung cancer the most common type of tumor to spread to the brain.
    explanation: This article further supports the statement by specifying the brain as a common site for metastasis of lung cancer.
  - reference: PMID:36269457
    reference_title: "Management and Treatment of Non-small Cell Lung Cancer with MET Alteration and Mechanisms of Resistance."
    supports: SUPPORT
    snippet: Pathologic activation of MET can be achieved with increased number of gene copies overexpression, or decreased protein degradation through several mechanisms, including mutations, amplifications, or fusions. Besides its role as primary driver, MET activation might also mediate resistance to kinase inhibitors in NSCLC with various other actionable alterations.
    explanation: Although primarily focused on MET-driven tumors, this article aligns with the statement by addressing the mechanisms of how NSCLC can become metastatic.
- name: EMT and Invasion
  conforms_to: "invasion_and_metastasis#Epithelial-Mesenchymal Transition Activation"
  description: >-
    NSCLC cells adopt EMT programs to detach from primary lesions, invade surrounding
    stroma,
    and survive transit to distant sites. EMT also contributes to resistance to targeted
    therapy and immune-mediated clearance.
  downstream:
  - target: Metastasis
    description: >-
      EMT-driven detachment, stromal invasion, and survival in transit are the
      upstream steps that enable dissemination and metastatic colonization of
      distant organs.
  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
  - preferred_term: positive regulation of cell migration
    modifier: INCREASED
    term:
      id: GO:0030335
      label: positive regulation of cell migration
- name: Brain Metastasis Seed-and-Soil Biology
  conforms_to: "invasion_and_metastasis#Circulatory Survival and Extravasation"
  description: >-
    Brain metastases arise when circulating NSCLC cells survive vascular arrest, cross
    the
    blood-brain barrier, and adapt to the neural microenvironment. Organ microenvironmental
    interactions are major determinants of treatment resistance in cerebral disease.
  evidence:
  - reference: PMID:26222080
    reference_title: "The Biology of Brain Metastasis: Challenges for Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These findings substantiate the importance of the "seed and soil" hypothesis and that successful treatment of brain metastases must include targeting of the organ microenvironment.
    explanation: This supports organ-specific microenvironmental control of NSCLC brain metastasis behavior.
  biological_processes:
  - preferred_term: cell migration
    modifier: INCREASED
    term:
      id: GO:0016477
      label: cell migration
histopathology:
- name: Adenocarcinoma Predominance
  finding_term:
    preferred_term: Lung Adenocarcinoma
    term:
      id: NCIT:C3512
      label: Lung Adenocarcinoma
  frequency: VERY_FREQUENT
  description: Adenocarcinoma is the most common histologic subtype in NSCLC.
  evidence:
  - reference: PMID:32657049
    reference_title: "Genetic profile of non-small cell lung cancer (NSCLC): A hospital-based survey in Jinhua."
    supports: SUPPORT
    snippet: "Of 256 patients with NSCLC, 219 were adenocarcinoma"
    explanation: Abstract reports a NSCLC cohort dominated by adenocarcinoma.

phenotypes:
- category: Respiratory
  name: Persistent Cough
  frequency: FREQUENT
  evidence:
  - reference: PMID:35224703
    reference_title: "Validation of the simplified cough symptom score in non-small cell lung cancer patients after surgery."
    supports: SUPPORT
    snippet: A total of 219 NSCLC patients completed the sCSS, Leicester Cough Questionnaire in Mandarin-Chinese (LCQ-MC) and cough Visual Analog Scale (VAS)... The sCSS is a reliable, valid instrument for assessing postoperative cough in NSCLC patients.
    explanation: This study supports that persistent cough is common in NSCLC patients.
  - reference: PMID:37920959
    reference_title: "Trajectories and risk factors of persistent cough after pulmonary resection: A prospective two-center study."
    supports: SUPPORT
    snippet: Persistent cough is one of the most frequent complications following lung cancer surgery. ... Multivariable regression analysis revealed that a duration of anesthesia exceeding 156 min ... and gastroesophageal acid reflux (GER) ... were independent risk factors of persistent CAP.
    explanation: This study confirms the high frequency of persistent cough in patients after lung cancer surgery, aligning with the statement that persistent cough is a common phenotype in NSCLC.
  - reference: PMID:29666219
    reference_title: "Symptoms at lung cancer diagnosis are associated with major differences in prognosis."
    supports: SUPPORT
    snippet: Compared with the cough-alone symptom group, the risks of dying or HRs were significantly higher for the groups presenting with breathlessness ..., systemic symptoms ..., weight loss ..., chest pain ..., cough with breathlessness ..., neurological symptoms ... and other symptom combinations ...
    explanation: While this study shows that cough is one of the symptoms among lung cancer patients, it does not explicitly address the commonality of persistent cough in NSCLC phenotypes.
- category: Respiratory
  name: Hemoptysis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:25359349
    reference_title: "Severe haemoptysis in patients with nonsmall cell lung carcinoma."
    supports: SUPPORT
    snippet: Severe haemoptysis due to nonsmall cell lung cancer (NSCLC) is considered a grim condition...
    explanation: The study confirms that hemoptysis is a recognized condition associated with non-small cell lung cancer (NSCLC).
  - reference: PMID:33563454
    reference_title: "Chronic Cough With Non-Resolving Mass-like Consolidation."
    supports: NO_EVIDENCE
    snippet: There was no associated hemoptysis, hoarseness, epistaxis, or fever on systemic review.
    explanation: The case report does not support the presence of hemoptysis in the specific instance of NSCLC described.
  - reference: PMID:34807953
    reference_title: "Respiratory symptoms and respiratory deaths: A multi-cohort study with 45 years observation time."
    supports: NO_EVIDENCE
    snippet: A positive association was observed between scores of respiratory symptoms and deaths due to COPD and lung cancer.
    explanation: The study does not specifically focus on hemoptysis as a symptom of NSCLC.
  phenotype_term:
    preferred_term: Hemoptysis
    term:
      id: HP:0002105
      label: Hemoptysis
- category: Systemic
  name: Weight Loss
  frequency: FREQUENT
  evidence:
  - reference: PMID:35468688
    reference_title: "Optimising Outcomes in Non Small Cell Lung Cancer: Targeting Cancer Cachexia."
    supports: SUPPORT
    snippet: One of the reasons patients with Non-Small Cell Lung Cancer are not fit for treatment is cancer cachexia, which is common (upto 75% of patients) in this group. This metabolic syndrome presents clinically as weight loss (muscle +/- fat), decreased physical function (patients less active) and anorexia on a background of systemic inflammation.
    explanation: The literature indicates that weight loss is a common symptom in Non-Small Cell Lung Cancer patients due to cancer cachexia.
  - reference: PMID:35559635
    reference_title: "Lung Cancer: Diagnosis, Treatment Principles, and Screening."
    supports: SUPPORT
    snippet: Associated symptoms, including hemoptysis or shortness of breath, or systemic symptoms, including anorexia or weight loss, greatly increase the likelihood of having lung cancer.
    explanation: The literature mentions weight loss as a common systemic symptom associated with lung cancer, supporting its prevalence in Non-Small Cell Lung Cancer.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
- category: Musculoskeletal
  name: Bone Pain
  frequency: OCCASIONAL
  notes: May indicate bone metastases
  evidence:
  - reference: PMID:20536932
    reference_title: "Bone cancer pain."
    supports: SUPPORT
    snippet: Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone.
    explanation: The reference states that bone cancer pain is common in patients with advanced lung cancer, including NSCLC, indicating bone metastases.
  - reference: PMID:26690845
    reference_title: "Natural History of Non-Small-Cell Lung Cancer with Bone Metastases."
    supports: SUPPORT
    snippet: We conducted a large, multicenter, retrospective survey aimed to explore the impact of tumor bone involvement in Non-Small Cell Lung Cancer... Bone metastases were evident at diagnosis in 57.5% of patients.
    explanation: This reference discusses the occurrence of bone metastases in NSCLC patients, which is linked to symptoms like bone pain.
  phenotype_term:
    preferred_term: Bone Pain
    term:
      id: HP:0002653
      label: Bone pain
- category: Systemic
  frequency: FREQUENT
  name: Fatigue
  evidence:
  - reference: PMID:38469616
    reference_title: "Longitudinal Study on Changes of Cancer-Related Fatigue in Elderly Patients with Postoperative Chemotherapy for Non-Small Cell Lung Cancer."
    supports: SUPPORT
    snippet: Cancer-related fatigue (CRF) stands out as one of the most prevalent subjective adverse reactions experienced by patients following chemotherapy, often resulting in unfavorable symptoms for elderly non-small cell lung cancer (NSCLC) patients during chemotherapy.
    explanation: The study highlights that cancer-related fatigue is a prevalent adverse reaction in elderly NSCLC patients undergoing chemotherapy.
  - reference: PMID:33755621
    reference_title: "New Adjuvant Drug for Lung Cancer."
    supports: SUPPORT
    snippet: The most common adverse effects of treatment are leukopenia, lymphopenia, thrombocytopenia, diarrhea, anemia, rash, musculoskeletal pain, nail toxicity, neutropenia, dry skin, stomatitis, fatigue, and cough.
    explanation: Fatigue is listed as one of the most common adverse effects of treatment for NSCLC.
  - reference: PMID:32013812
    reference_title: "Exhaustive Review on Lung Cancers: Novel Technologies."
    supports: SUPPORT
    snippet: During the early stage, there is no perspicuous sign/symptoms but later many symptoms emerge in the infected individual such as insomnia, headache, pain, loss of appetite, fatigue, coughing etc.
    explanation: Fatigue is mentioned as a symptom that emerges in individuals with lung cancer, including NSCLC.
  - reference: PMID:26990789
    reference_title: "Health state utilities in non-small cell lung cancer: An international study."
    supports: SUPPORT
    snippet: Toxicities included neutropenia, febrile neutropenia, fatigue, diarrhea, nausea and vomiting, rash, bleeding, hypertension, and hair loss.
    explanation: Fatigue is listed as one of the common grade III/IV toxicities associated with treatment for metastatic NSCLC.
  - reference: PMID:30537755
    reference_title: "Efficacy and Safety of Amrubicin in Non-Small-Cell Lung Cancer Patients Beyond Third-Line Therapy."
    supports: SUPPORT
    snippet: Non-hematological toxicities of >/= grade 2 included anorexia (27.5%) and fatigue (24.6%).
    explanation: Fatigue is noted as a non-hematological toxicity in NSCLC patients beyond third-line therapy.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- category: Musculoskeletal
  frequency: OCCASIONAL
  name: Bone Pain
  notes: May indicate bone metastases
  evidence:
  - reference: PMID:26690845
    reference_title: "Natural History of Non-Small-Cell Lung Cancer with Bone Metastases."
    supports: SUPPORT
    snippet: Bone metastases were evident at diagnosis in 57.5% of patients. In the remaining cases median time to bone metastases appearance was 9 months. ... Skeletal-related events were experienced by 57.7% of patients; the most common was the need for radiotherapy.
    explanation: The reference indicates that bone metastases are common in NSCLC patients, and skeletal-related events are frequent. However, it does not explicitly categorize bone pain as 'occasional.'
  - reference: PMID:20536932
    reference_title: "Bone cancer pain."
    supports: SUPPORT
    snippet: Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone.
    explanation: The reference supports that bone pain is common in lung cancer with bone metastases, but it does not specify the frequency as 'occasional.'
  - reference: PMID:27988895
    reference_title: "Radiopharmaceuticals for metastatic bone pain palliation: available options in the clinical domain and their comparisons."
    supports: SUPPORT
    snippet: Bone pain arising due to skeletal metastases is one of the common complications experienced by the majority of patients suffering from prostate, breast and lung cancer at the advanced stage of the disease.
    explanation: This reference supports the statement that bone pain is a common complication in advanced lung cancer with skeletal metastases, aligning with the note that it may indicate bone metastases.
  phenotype_term:
    preferred_term: Bone Pain
    term:
      id: HP:0002653
      label: Bone pain
- category: Respiratory
  frequency: OCCASIONAL
  name: Chest Pain
  evidence:
  - reference: PMID:27466520
    reference_title: "Symptom Assessment for Patients with Non-small Cell Lung Cancer Scheduled for Chemotherapy."
    supports: NO_EVIDENCE
    snippet: The most prevalent symptoms were coughing (EORTC score 41.7), dyspnea (33.9), fatigue (31.9), insomnia (30.3) and pain (21.8).
    explanation: The study lists pain as one of the prevalent symptoms but does not specify chest pain or its frequency.
  - reference: PMID:20536932
    reference_title: "Bone cancer pain."
    supports: NO_EVIDENCE
    snippet: Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone.
    explanation: The study discusses bone cancer pain in the context of lung cancer metastasis but does not mention chest pain or its frequency.
  phenotype_term:
    preferred_term: Chest pain
    term:
      id: HP:0100749
      label: Chest pain
- category: Respiratory
  frequency: OCCASIONAL
  name: Recurrent Pneumonia
  notes: Due to airway obstruction by tumor
  evidence:
  - reference: PMID:23857204
    reference_title: "The microbiology of postobstructive pneumonia in lung cancer patients."
    supports: SUPPORT
    snippet: Recurrent pneumonias often occur in the setting of an airway obstruction and can be the presenting symptom of an undiagnosed malignancy.
    explanation: The abstract mentions that recurrent pneumonias often occur due to airway obstruction, which can be a symptom of lung cancer.
  - reference: PMID:15723108
    reference_title: "[Respiratory emergencies]."
    supports: SUPPORT
    snippet: Obstruction of the airway should be initially evaluated with endoscopic procedures.
    explanation: This reference supports the statement by indicating that airway obstruction, which can be caused by tumors, is a concern in respiratory emergencies in cancer patients.
  phenotype_term:
    preferred_term: Recurrent Pneumonia
    term:
      id: HP:0006532
      label: Recurrent pneumonia
- category: Neurologic
  frequency: OCCASIONAL
  name: Headache
  notes: May indicate brain metastases
  evidence:
  - reference: PMID:29484515
    reference_title: "Early stage non-small cell lung cancer patients need brain imaging regardless of symptoms."
    supports: SUPPORT
    snippet: However, brain metastasis sometimes occurs in early stage NSCLC patients without any neurological symptoms.
    explanation: The reference indicates that brain metastasis can occur in NSCLC patients, often without neurological symptoms. However, it does not specifically mention headache as an occasional symptom.
  - reference: PMID:11754303
    reference_title: "Remote neurologic manifestations of cancer."
    supports: NO_EVIDENCE
    snippet: Paraneoplastic disorders may affect any part of the central or peripheral nervous systems.
    explanation: The reference discusses paraneoplastic disorders affecting the nervous system but does not specifically mention headache as a symptom of NSCLC.
  - reference: PMID:15056056
    reference_title: "Brain metastases in lung cancer."
    supports: SUPPORT
    snippet: Brain metastases secondary to primary non-small cell and small cell lung cancer have become an important area of research.
    explanation: The reference discusses brain metastases in NSCLC but does not specifically mention headache as an occasional symptom.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
- category: Respiratory
  name: Dyspnea
  frequency: VERY_FREQUENT
  description: Dyspnea reflects thoracic disease burden, pleural disease, or lymphangitic spread.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
biochemical:
- name: Carcinoembryonic Antigen
  synonyms:
  - CEA
  presence: Elevated
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:37390106
    reference_title: "Prognostic Value of Pretreatment Serum Carcinoembryonic Antigen Level in 1130 Patients With Non-small Cell Lung Cancer: A Propensity Score Matching Cohort Study and Cumulative Meta-analysis."
    supports: SUPPORT
    snippet: Carcinoembryonic antigen (CEA) is the most frequently used tumor marker for non-small cell lung cancer (NSCLC).
    explanation: The reference discusses the use of CEA as a tumor marker in NSCLC, indicating its relevance and occasional elevated presence.
- name: Cytokeratin Fragment 21-1
  synonyms:
  - CYFRA 21-1
  presence: Elevated
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:8709175
    reference_title: "Cytokeratin fragment 19 (CYFRA 21-1) as a tumor marker in non-small cell lung cancer."
    supports: SUPPORT
    snippet: The mean (SD) value of serum CYFRA 21-1 in NSCLC (13.26 (16.54)) was significantly higher than in benign lung diseases (1.74 (1.55)) (p < 0.0001).
    explanation: CYFRA 21-1 levels are elevated in NSCLC patients, supporting the statement of its occasional presence in a biochemical context.
genetic:
- name: EGFR
  gene_term:
    preferred_term: EGFR
    term:
      id: hgnc:3236
      label: EGFR
  association: Activating Mutations
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:23647298
    reference_title: "Rare mutations in non-small-cell lung cancer."
    supports: SUPPORT
    snippet: EGFR mutations are a relatively frequent event in non-small-cell lung cancer, generally consisting of exon 19 deletion or exon 21 substitution. In adenocarcinoma, additional rare mutations are detectable in the EGFR gene.
    explanation: The reference indicates that EGFR mutations, including activating mutations, are a frequent event, which matches the statement that such mutations occur occasionally.
  - reference: PMID:27926500
    reference_title: "The association between clinical prognostic factors and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) efficacy in advanced non-small-cell lung cancer patients: a retrospective assessment of 94 cases with EGFR mutations."
    supports: SUPPORT
    snippet: The results of this study demonstrate that EGFR-TKI therapy results in survival benefits for EGFR-mutant advanced NSCLC patients, regardless of gender, smoking history, pathologic type, type of EGFR mutations, brain metastasis and timing of targeted therapy.
    explanation: This study further supports the association of EGFR activating mutations in NSCLC and the effectiveness of targeted therapies, implying the commonality and impact of these mutations.
  - reference: PMID:32107398
    reference_title: "Identifying relationships between imaging phenotypes and lung cancer-related mutation status: EGFR and KRAS."
    supports: SUPPORT
    snippet: EGFR mutation status might be correlated to CT scans imaging phenotypes.
    explanation: The research recognizes the frequent mutations in EGFR, validating the association stated in the provided statement.
  - reference: PMID:30520383
    reference_title: "Advanced Non-Small Cell Lung Cancer with Activating Epidermal Growth Factor Receptor Mutation: First Line Treatment and Beyond."
    supports: SUPPORT
    snippet: Moreover, 10 to 15% of all NSCLCs harbor EGFR (epidermal growth factor receptor) activating mutations.
    explanation: The frequency (10-15%) explicitly mentioned aligns well with the occasional occurrence stated in the statement.
  - reference: PMID:18957054
    reference_title: "Association of epidermal growth factor receptor (EGFR) gene mutations with EGFR amplification in advanced non-small cell lung cancer."
    supports: SUPPORT
    snippet: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the response to EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer.
    explanation: The reference confirms that activating mutations in EGFR are significant and frequent enough to impact treatment and response, supporting the statement's claim.
  - reference: PMID:32657049
    reference_title: "Genetic profile of non-small cell lung cancer (NSCLC): A hospital-based survey in Jinhua."
    supports: SUPPORT
    snippet: We describe the clinical features, genetic profile, and their correlation in NSCLC patients... The frequency of mutations in EGFR, MET, and RET were significantly higher in nonsmokers than in smokers.
    explanation: By describing EGFR mutations as a notable factor linked with clinical and demographic attributes of NSCLC patients, it supports the occasional frequency mentioned in the statement.
  - reference: PMID:23621221
    reference_title: "Correlation between EGFR mutations and serum tumor markers in lung adenocarcinoma patients."
    supports: SUPPORT
    snippet: Mutations affecting the epidermal growth factor receptor (EGFR) are good predictors of clinical efficacy of EGFR tyrosine kinase inhibitors (TKI) in patients with non-small cell lung cancer.
    explanation: The study acknowledges the association of EGFR mutations with clinical outcomes in NSCLC, supporting the idea of their occasional prevalence.
  - reference: CGGV:assertion_49342c73-96d7-45ba-9c90-d2d5e5710636-2020-07-30T202207.418Z
    reference_title: "EGFR / non-small cell lung carcinoma (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "EGFR | HGNC:3236 | non-small cell lung carcinoma | MONDO:0005233 | AD | Definitive"
    explanation: ClinGen classifies the EGFR-non-small cell lung carcinoma gene-disease relationship as definitive with autosomal dominant inheritance.
- name: ALK
  gene_term:
    preferred_term: ALK
    term:
      id: hgnc:427
      label: ALK
  association: Gene Rearrangements
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30878128
    reference_title: "ALK rearrangements: Biology, detection and opportunities of therapy in non-small cell lung cancer."
    supports: SUPPORT
    snippet: The ALK receptor tyrosine kinase (ALK) gene encodes a transmembrane protein rearranged in 2-7% of non-small cell lung cancer (NSCLC) cases.
    explanation: The literature describes ALK rearrangements occurring in 2-7% of NSCLC cases, supporting the statement that ALK rearrangements are occasional in frequency in NSCLC.
  - reference: PMID:35986977
    reference_title: "Common genetic driver mutation in NSCLC and their association with thromboembolic events: A retrospective study."
    supports: SUPPORT
    snippet: the presence of ALK/ROS rearrangements in our study is associated with an approximately threefold to fourfold increase in thrombosis risk in NSCLC patients.
    explanation: The mention of ALK rearrangements aligns with the statement indicating that they are a recognised genetic association in NSCLC.
  - reference: PMID:36806787
    reference_title: "Rare molecular subtypes of lung cancer."
    supports: SUPPORT
    snippet: more commonly recognized alterations (such as KRAS, BRAF, MET and ERBB family mutations, or ALK, RET and ROS1 fusions)
    explanation: The literature identifies ALK rearrangements as part of more commonly recognized alterations/subtypes in NSCLC, supporting their occasional occurrence.
- name: ROS1
  gene_term:
    preferred_term: ROS1
    term:
      id: hgnc:10261
      label: ROS1
  association: Gene Rearrangements
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35200557
    reference_title: "ROS-1 Fusions in Non-Small-Cell Lung Cancer: Evidence to Date."
    supports: SUPPORT
    snippet: ROS-1 rearrangement is found in 0.9-2.6% of non-small-cell lung cancers (NSCLCs), mostly lung adenocarcinomas.
    explanation: The literature states that ROS-1 rearrangement occurs in a small percentage of NSCLCs, supporting the statement that ROS1 gene rearrangements are occasional in NSCLC.
  - reference: PMID:35986977
    reference_title: "Common genetic driver mutation in NSCLC and their association with thromboembolic events: A retrospective study."
    supports: SUPPORT
    snippet: ROS and ALK rearrangement is highly associated with TE development, with HR of 4.04 ... p = 0.005
    explanation: The literature mentions ROS1 rearrangements in the context of their association with thromboembolic events, indicating the presence and relevance of these genetic alterations in NSCLC.
  - reference: PMID:34325210
    reference_title: "Relationship between clinical features and gene mutations in non-small cell lung cancer with osteoblastic bone metastasis."
    supports: SUPPORT
    snippet: We investigated the clinical characteristics and gene mutation rate of non-small cell lung cancer patients with osteoblastic bone metastases at the time of the initial diagnosis. ... two were ROS1 rearrangement-positive.
    explanation: This reference confirms the presence of ROS1 rearrangements in a subgroup of NSCLC patients, which aligns with the statement regarding the occasional frequency of these rearrangements.
  - reference: PMID:36806787
    reference_title: "Rare molecular subtypes of lung cancer."
    supports: SUPPORT
    snippet: Less commonly identified alterations (such as...ROS1 fusions).
    explanation: The literature identifies ROS1 fusions as less common alterations in NSCLC, which supports the occasional occurrence of these gene rearrangements.
- name: KRAS
  gene_term:
    preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  association: Activating Mutations
  frequency: OCCASIONAL
  notes: Co-mutation with STK11 and/or KEAP1 predicts cold tumor microenvironment and inferior response to immune checkpoint inhibitors
  evidence:
  - reference: PMID:33618059
    reference_title: "KRAS G12C-Mutant Non-Small Cell Lung Cancer: Biology, Developmental Therapeutics, and Molecular Testing."
    supports: SUPPORT
    snippet: Mutation in the gene that encodes Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogenic driver in advanced non-small cell lung cancer, occurring in approximately 30% of lung adenocarcinomas.
    explanation: This reference confirms that KRAS activating mutations are present in non-small cell lung cancer (NSCLC).
  - reference: PMID:23723294
    reference_title: "Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap)."
    supports: SUPPORT
    snippet: Although EGFR mutations were most frequent in patients with ADC and never/light smokers from Asia, and KRAS mutations were most frequent in patients with ADC and ever/heavy smokers from Western countries, both were detected outside these subgroups.
    explanation: This reference supports the occurrence of KRAS mutations in NSCLC, indicating they are within a notable frequency and linked to specific subgroups.
  - reference: PMID:31862576
    reference_title: "Concomitant genomic alterations in KRAS mutant advanced lung adenocarcinoma."
    supports: SUPPORT
    snippet: KRAS mutations are one of the most prevalent alterations in non-small cell lung cancer.
    explanation: This reference reiterates the frequent nature of KRAS mutations in NSCLC, aligning with the "occasional" frequency stated.
- name: STK11
  gene_term:
    preferred_term: STK11
    term:
      id: hgnc:11389
      label: STK11
  association: Loss-of-function Mutations
  frequency: OCCASIONAL
  notes: Co-mutation with KRAS creates metabolic dependency on G6PD/PPP pathway; associated with cold tumor microenvironment and poor ICI response; dual PD-L1/CTLA-4 blockade may partially overcome resistance
- name: KEAP1
  gene_term:
    preferred_term: KEAP1
    term:
      id: hgnc:23177
      label: KEAP1
  association: Loss-of-function Mutations
  frequency: OCCASIONAL
  notes: Activates NRF2 antioxidant pathway; independent adverse prognostic factor for OS on ICIs (HR 1.890); co-mutation with KRAS predicts ICI resistance; dual PD-L1/CTLA-4 blockade may provide benefit
- name: TP53
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  association: Loss-of-function Mutations
  frequency: FREQUENT
  notes: Independent adverse prognostic factor for OS on ICIs (HR 1.735); associated with higher tumor mutational burden; variable impact on ICI outcomes depending on co-mutation context
- name: G6PD
  gene_term:
    preferred_term: G6PD
    term:
      id: hgnc:4057
      label: G6PD
  association: Metabolic Dependency
  frequency: OCCASIONAL
  notes: KRAS/LKB1 co-mutant tumors show selective dependency on G6PD for NADPH generation and lipogenesis; genetic ablation activates p53 and suppresses tumorigenesis
environmental:
- name: Smoking
  notes: Major risk factor, particularly for squamous cell carcinoma
  evidence:
  - reference: PMID:27188576
    reference_title: "Non-small-cell lung cancer."
    supports: SUPPORT
    snippet: Non-small-cell lung cancer (NSCLC), a heterogeneous class of tumours, represents approximately 85% of all new lung cancer diagnoses. Tobacco smoking remains the main risk factor for developing this disease.
    explanation: This reference explicitly mentions tobacco smoking as the main risk factor for non-small cell lung cancer.
  - reference: PMID:24976334
    reference_title: "The prognostic impact of the amount of tobacco smoking in non-small cell lung cancer--differences between adenocarcinoma and squamous cell carcinoma."
    supports: SUPPORT
    snippet: The never-smokers had a significantly better prognosis than ever-smokers among Ad patients, whereas the light-smokers had a significantly worse prognosis than heavy smokers among Sq patients.
    explanation: This study emphasizes the relationship between smoking and prognosis in different types of NSCLC, indicating that smoking is a significant factor.
  - reference: PMID:9498897
    reference_title: "Risk of lung cancer from environmental exposures to tobacco smoke."
    supports: SUPPORT
    snippet: Tobacco smoke has been shown to increase the risk of lung cancer down to the lowest exposure levels. Environmental tobacco smoke contains the same carcinogenic compounds as those found in the tobacco smoke inhaled directly by the smoker.
    explanation: This reference discusses the carcinogenic effects of tobacco smoke, affirming its role as a risk factor for lung cancer.
  - reference: PMID:34083039
    reference_title: "Relationships among smoking, oxidative stress, inflammation, macromolecular damage, and cancer."
    supports: SUPPORT
    snippet: Smoking is a major risk factor for a variety of diseases, including cancer and immune-mediated inflammatory diseases. Tobacco smoke contains a mixture of chemicals, including a host of reactive oxygen- and nitrogen species (ROS and RNS), among others, that can damage cellular and sub-cellular targets.
    explanation: This review covers the role of smoking in cancer development, highlighting its significance as a risk factor due to the oxidative stress and inflammation it causes.
  - reference: PMID:19020892
    reference_title: "Major histopathological patterns of lung cancer related to arsenic exposure in German uranium miners."
    supports: SUPPORT
    snippet: Arsenic exposure was associated with non-small cell lung cancer. Silicosis turned out as major determinant of the cell type related with arsenic.
    explanation: Although the focus is on arsenic exposure, the study indicates that non-small cell lung cancer can be associated with environmental carcinogens including tobacco.
  - reference: PMID:15886304
    reference_title: "Epidemiology of lung cancer: looking to the future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cigarette smoking was identified as the single most predominant cause of the lung cancer epidemic"
    explanation: Establishes tobacco smoking as the dominant risk factor for lung cancer; folded in from the former Metastatic_NSCLC entry.
  exposure_term:
    preferred_term: Tobacco smoking exposure
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
- name: Radon Exposure
  influences_mechanisms:
  - target: Oncogenic Driver Mutations
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inhaled radon progeny irradiate bronchial epithelium with alpha
      particles, but the cited evidence is deliberately hedged and is
      qualified to current smokers at high residential concentrations, with
      the risk in never-smokers left unresolved. Recorded as a susceptibility
      contribution rather than an established mutational route.
    evidence:
    - reference: PMID:12075673
      reference_title: "Residential radon exposure and lung cancer: risk in nonsmokers."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Based on the most recent findings, there is some evidence that radon may contribute to lung cancer risk in current smokers in high residential radon environments... The situation regarding the risk of lung cancer from radon in non-smokers (ex and never) is unclear."
      explanation: >-
        States there is some evidence that radon may contribute to lung cancer
        risk in current smokers at high residential concentrations, while
        noting the risk in non-smokers is unclear.
  notes: Increases risk, especially in combination with smoking
  evidence:
  - reference: PMID:12075673
    reference_title: "Residential radon exposure and lung cancer: risk in nonsmokers."
    supports: SUPPORT
    snippet: Based on the most recent findings, there is some evidence that radon may contribute to lung cancer risk in current smokers in high residential radon environments... The situation regarding the risk of lung cancer from radon in non-smokers (ex and never) is unclear.
    explanation: There is evidence that radon exposure may increase lung cancer risk in smokers, but the evidence for non-smokers is unclear.
  - reference: PMID:38159450
    reference_title: "Radon activity concentration RnCA and workers lung cancer risks in SENA coal mines, Colombia."
    supports: SUPPORT
    snippet: Miners increased risk of contracting lung cancer is included. It is concluded that the mine ventilation system satisfies the conditions required by the current radiological protection of the miners.
    explanation: This study discusses the increased risk of lung cancer associated with radon exposure for underground workers, which supports the link between radon and lung cancer risk.
  - reference: PMID:20429156
    reference_title: "Environmental factors in cancer: radon."
    supports: NO_EVIDENCE
    snippet: Environmental factors in cancer... radon.
    explanation: The provided literature does not contain any detailed content to evaluate the support of the statement.
  - reference: PMID:25351923
    reference_title: "Comparative pathobiology of environmentally induced lung cancers in humans and rodents."
    supports: SUPPORT
    snippet: Human lung cancers are phenotypically more diverse and broadly constitute 2 types... small cell lung cancers and nonsmall cell lung cancers (NSCLCs). ... especially in lung cancers resulting from exposure to environmental carcinogens.
    explanation: The reference supports the association between environmental agents, including radon, and non-small cell lung cancer.
  exposure_term:
    preferred_term: Radon exposure
    term:
      id: ECTO:9000097
      label: exposure to radon
- name: Household Smoky Coal Combustion
  notes: >-
    Domestic (indoor, unvented) burning of "smoky" bituminous coal for cooking
    and heating, the exposure behind the lung cancer incidence in Xuanwei
    County, Yunnan, China — the highest in the country and largely in
    never-smoking women. It is curated as a distinct exposure rather than as a
    variant of tobacco or generic air pollution because the comparison that
    isolates it is within-population: lifelong users of smoky (bituminous) coal
    versus lifelong users of smokeless (anthracite) coal in the same county,
    which controls for tobacco, geography, and diet.
  influences_mechanisms:
  - target: Oncogenic Driver Mutations
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Coal-smoke polycyclic aromatic hydrocarbons — principally benzo[a]pyrene
      and methylated PAHs such as 5-methylchrysene — are the exposures that
      best explain risk in this population, and the resulting tumours carry a
      correspondingly distinct mutational spectrum: excess C:G to A:T
      transversions, a markedly higher mutated-gene count than tumours from
      control regions, and a BaP-attributed EGFR-G719X hotspot. The edge is
      typed INDIRECT_KNOWN_INTERMEDIATES rather than DIRECT because the
      intervening steps (PAH metabolic activation, bulky DNA adduct formation,
      error-prone bypass) are established chemistry that this entry does not
      model as its own nodes; the Xuanwei-specific attribution itself rests on
      mutational-signature inference, not on experimental demonstration in
      these patients.
    evidence:
    - reference: PMID:26288819
      reference_title: "Characterization of Somatic Mutations in Air Pollution-Related Lung Cancer."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Whole genome sequencing revealed a mean of 289 somatic exonic mutations per tumor and the frequent C:G → A:T nucleotide substitutions in Xuanwei NSCLCs."
      explanation: >-
        Sequencing of 164 NSCLCs from Xuanwei versus control regions where smoky
        coal was not used shows the exposure leaves a distinct somatic mutation
        spectrum, which is the mutational route from this exposure to the driver
        lesions modelled on the target node.
    - reference: PMID:39432560
      reference_title: "Proteogenomic analysis of air-pollution-associated lung cancer reveals prevention and therapeutic opportunities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The BaP-induced mutation hotspot, EGFR-G719X, was present in 20% of XWLC which endowed XWLC with elevated MAPK pathway activations and worse outcomes compared to common EGFR mutations."
      explanation: >-
        Ties the exposure to a specific driver allele and to the MAPK cascade
        already curated on the Oncogenic Driver Mutations node, in a cohort of
        169 female never-smokers where coal smoke is the dominant exposure.
    - reference: PMID:36921559
      reference_title: "Methylated polycyclic aromatic hydrocarbons from household coal use across the life course and risk of lung cancer in a large cohort of 42,420 subjects in Xuanwei, China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We confirmed the link between PAH exposures and lung cancer in smoky coal users and found exposures before age 18 to be especially important."
      explanation: >-
        Identifies PAHs as the carcinogenic constituent of the exposure, which
        is what makes the mutational-signature attribution in the two genomic
        studies mechanistically coherent rather than merely correlative.
  evidence:
  - reference: PMID:22936785
    reference_title: "Risk of lung cancer associated with domestic use of coal in Xuanwei, China: retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In Xuanwei, the domestic use of smoky coal is associated with a substantial increase in the absolute lifetime risk of developing lung cancer and is likely to represent one of the strongest effects of environmental pollution reported for cancer risk."
    explanation: >-
      Retrospective cohort of 27,310 lifelong smoky-coal users versus 9,962
      lifelong smokeless-coal users establishes the exposure as a lung cancer
      risk factor with the smoky-versus-smokeless contrast controlling for the
      shared local environment.
  - reference: PMID:22936785
    reference_title: "Risk of lung cancer associated with domestic use of coal in Xuanwei, China: retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The absolute risks of lung cancer death before 70 years of age for men and women using smoky coal were 18% and 20%, respectively, compared with less than 0.5% among smokeless coal users of both sexes."
    explanation: >-
      Quantifies the effect size, and shows it is not sex-restricted despite the
      genomic cohorts being drawn predominantly from never-smoking women.
  - reference: PMID:26288819
    reference_title: "Characterization of Somatic Mutations in Air Pollution-Related Lung Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In Xuanwei City of Yunnan Province, the lung cancer incidence is among the highest in China attributed to severe air pollution generated by combustion of smoky coal"
    explanation: >-
      Independent statement attributing the regional incidence to smoky-coal
      combustion, from a genomics rather than an epidemiology group.
  exposure_term:
    preferred_term: Household smoky (bituminous) coal combustion exposure
    term:
      id: ECTO:7000004
      label: exposure to coal
treatments:
- name: Surgery
  description: Lobectomy or pneumonectomy for localized disease
  evidence:
  - reference: PMID:11720753
    reference_title: "Surgery for non-small cell lung cancer."
    supports: SUPPORT
    snippet: Surgical resection remains the treatment of choice for early stage non-small cell lung cancer (NSCLC). In stages IA, IB, IIA, IIB and selected stages IIIA surgical treatment offers the best long-term prognosis when a complete resection can be performed. Standard operations include lobectomy, bilobectomy and pneumonectomy.
    explanation: This indicates that lobectomy and pneumonectomy are standard surgical treatments for localized non-small cell lung cancer.
  - reference: PMID:37625619
    reference_title: "Lobectomy versus proton therapy for stage I non-small cell lung cancer."
    supports: SUPPORT
    snippet: Lobectomy is the standard treatment for patients with early-stage non-small cell lung cancer (NSCLC).
    explanation: This further reinforces that lobectomy, a type of surgery, is a standard treatment for localized non-small cell lung cancer.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
- name: Chemotherapy
  description: Platinum-based chemotherapy (cisplatin or carboplatin) in combination with other agents
  evidence:
  - reference: PMID:12094333
    reference_title: "Present and future treatment of advanced non-small cell lung cancer."
    supports: SUPPORT
    snippet: Platinum-based chemotherapy is considered the standard treatment for advanced non-small cell lung cancer (NSCLC). Several phase II trials using cisplatin in combination with new chemotherapeutic agents, such as gemcitabine, the taxanes, vinorelbine, and irinotecan, showed impressive response rates and suggested an improvement in overall survival.
    explanation: This supports the statement that platinum-based chemotherapy (specifically cisplatin) in combination with other agents is a treatment for NSCLC.
  - reference: PMID:1329222
    reference_title: "Carboplatin in non-small cell lung cancer: an update on the Cancer and Leukemia Group B experience."
    supports: SUPPORT
    snippet: '... carboplatin, either alone or in combination, in five separate phase II studies for patients with inoperable non-small cell lung cancer (NSCLC). ... Subsequently, combinations of carboplatin/cisplatin, carboplatin/etoposide, and carboplatin/vinblastine have been evaluated in similar patient groups.'
    explanation: This supports the statement as it mentions that carboplatin, either alone or in combination with other agents, is used in the treatment of NSCLC.
  - reference: PMID:26775594
    reference_title: "Cisplatin and carboplatin-based chemotherapy in the first-line treatment of non-small cell lung cancer: Analysis from the European FRAME study."
    supports: SUPPORT
    snippet: Of the 1564 patients who were included in the prospective study, 1520 received either cisplatin (54%) or carboplatin (46%) in combination with pemetrexed, gemcitabine, taxanes or vinorelbine.
    explanation: The study provides evidence that both cisplatin and carboplatin, in combination with other agents, are used in the treatment of NSCLC.
  - reference: PMID:35525024
    reference_title: "Pharmacological ascorbate improves the response to platinum-based chemotherapy in advanced stage non-small cell lung cancer."
    supports: SUPPORT
    snippet: Platinum-based chemotherapy with or without immunotherapy is the mainstay of treatment for advanced stage non-small cell lung cancer (NSCLC) lacking a molecular driver alteration.
    explanation: The mention of platinum-based chemotherapy (cisplatin or carboplatin) as a primary treatment supports the statement.
  - reference: PMID:27166967
    reference_title: "Can we predict the development of serious adverse events (SAEs) and early treatment termination in elderly non-small cell lung cancer (NSCLC) patients receiving platinum-based chemotherapy?"
    supports: SUPPORT
    snippet: Predicting the feasibility of platinum-based chemotherapy remains an important issue in elderly (over 70 years) patients with non-small cell lung cancer (NSCLC).
    explanation: This statement supports the use of platinum-based chemotherapy in the treatment of NSCLC, emphasizing its importance even in elderly patients.
  treatment_term:
    preferred_term: Chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
- name: Targeted Therapy
  description: Drugs targeting specific mutations, such as EGFR inhibitors (erlotinib, gefitinib), ALK inhibitors (crizotinib, ceritinib), and ROS1 inhibitors (crizotinib)
  evidence:
  - reference: PMID:34154330
    reference_title: "Targeted therapy of non-small cell lung cancer."
    supports: SUPPORT
    snippet: The review article presents the current state and development of the treatment with tyrosine kinase inhibitors in advanced non-small cell lung cancer. It focuses on the therapeutic progress of traditionally targeted gene mutations EGFR, ALK and ROS1.
    explanation: The reference discusses EGFR, ALK, and ROS1 inhibitors as targeted therapies for non-small cell lung cancer.
  - reference: PMID:15946581
    reference_title: "Epidermal growth factor receptor inhibitors and their role in non-small-cell lung cancer."
    supports: SUPPORT
    snippet: The epidermal growth factor receptor (EGFR) is a promising target in the treatment of advanced stage non-small-cell lung cancer (NSCLC). Currently erlotinib and gefitinib are approved by the US Food and Drug Administration.
    explanation: The reference discusses erlotinib and gefitinib as EGFR inhibitors used in the treatment of non-small cell lung cancer.
  - reference: PMID:22932130
    reference_title: "Targeted therapy for lung cancer."
    supports: SUPPORT
    snippet: Both erlotinib and crizotinib have been shown to be effective and safe for subgroup populations, and now personalized treatment for nonsquamous NSCLC has progressed even further.
    explanation: The reference confirms the use of erlotinib (EGFR inhibitor) and crizotinib (ALK and ROS1 inhibitor) in targeted therapy for non-small cell lung cancer.
  - reference: PMID:25240504
    reference_title: "Treatment algorithm in 2014 for advanced non-small cell lung cancer: therapy selection by tumour histology and molecular biology."
    supports: SUPPORT
    snippet: The availability of ... the EGFR-tyrosine kinase inhibitors erlotinib, gefitinib, afatinib as well as ... the ALK-inhibitor crizotinib has recently changes the treatment algorithm of advanced non-small cell lung cancer.
    explanation: The reference mentions the use of EGFR inhibitors (erlotinib, gefitinib) and ALK inhibitor (crizotinib) in treating non-small cell lung cancer.
  - reference: PMID:25322323
    reference_title: "ALK inhibitors in non-small cell lung cancer: crizotinib and beyond."
    supports: SUPPORT
    snippet: The treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small molecule inhibitor of the tyrosine kinases ALK, ROS1, and MET.
    explanation: The reference discusses crizotinib as an ALK and ROS1 inhibitor used in the treatment of non-small cell lung cancer.
  - reference: PMID:27491402
    reference_title: "EGFR and EML4-ALK Updated Therapies in Non-Small Cell Lung Cancer."
    supports: SUPPORT
    snippet: 'Currently, EGFR TKIs (e.g.: erlotinib, gefitinib, osimertinib) and ALK inhibitors (crizotinib, ceritinib, alectinib) provided a new face for advanced NSCLC outcomes.'
    explanation: The reference supports the use of EGFR inhibitors (erlotinib, gefitinib) and ALK inhibitors (crizotinib, ceritinib) in the treatment of non-small cell lung cancer.
  - reference: PMID:34125313
    reference_title: "ROS1 Targeted Therapies: Current Status."
    supports: SUPPORT
    snippet: 'Four FDA-approved drugs have significant activity against ROS1+ NSCLC: crizotinib, ciritinib, lorlatinib, and entrectinib.'
    explanation: The reference mentions crizotinib among the ROS1 inhibitors used for treating non-small cell lung cancer.
  - reference: PMID:28089942
    reference_title: "Targeting EGFR T790M mutation in NSCLC: From biology to evaluation and treatment."
    supports: SUPPORT
    snippet: Nowadays, different EGFR TKIs as afatinib, erlotinib and gefitinib are approved worldwide for the treatment of NSCLC harbouring EGFR mutations, in particular exon 19 deletions or exon 21 (Leu858Arg) substitution EGFR mutations.
    explanation: The reference discusses the use of EGFR inhibitors (erlotinib, gefitinib) in the treatment of non-small cell lung cancer.
  - reference: PMID:29020635
    reference_title: "Human Organ Chip Models Recapitulate Orthotopic Lung Cancer Growth, Therapeutic Responses, and Tumor Dormancy In Vitro."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: microfluidic organ-on-a-chip (organ chip) cell culture technology can be used to create in vitro human orthotopic models of non-small-cell lung cancer (NSCLC) that recapitulate organ microenvironment-specific cancer growth, tumor dormancy, and responses to tyrosine kinase inhibitor (TKI) therapy observed in human patients in vivo
    explanation: New Approach Methodology (NAM) evidence (Wyss Institute organ-on-chip work, in the spirit of the NAMeRS 2026 symposium) — a human lung organ-on-chip recapitulates NSCLC tyrosine kinase inhibitor therapeutic responses in vitro, with EGFR/MET-mediated TKI resistance, tumor dormancy, and persister-cell behavior, providing a microphysiological model of targeted-therapy response and acquired resistance without animal testing.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
- name: Immunotherapy
  description: Checkpoint inhibitors (nivolumab, pembrolizumab) for tumors with high PD-L1 expression
  evidence:
  - reference: PMID:28059852
    reference_title: "Immune checkpoint inhibitors in first-line therapy of advanced non-small cell lung cancer."
    supports: SUPPORT
    snippet: In accordance with recent results, US Food and Drug Administration approved a checkpoint inhibitor for first-line treatment of metastatic non-small cell lung cancer whose tumors have high PD-L1 expression, and European Medicines Agency approval is expected in early 2017.
    explanation: The FDA has approved immune checkpoint inhibitors for first-line treatment of metastatic NSCLC with high PD-L1 expression, supporting the use of immunotherapy (including nivolumab and pembrolizumab) for these patients.
  - reference: PMID:26927720
    reference_title: "Non-Small Cell Lung Cancer, PD-L1, and the Pathologist."
    supports: SUPPORT
    snippet: Data so far available show some conflicting results, but PD-L1 immunohistochemistry looks likely to be introduced into clinical use for selecting patients for treatment with anti-PD-1 or anti-PD-L1 therapies.
    explanation: The mention of PD-L1 immunohistochemistry being introduced for clinically selecting patients for anti-PD-1 therapies supports the statement.
  - reference: PMID:32189549
    reference_title: "Treatment beyond progression with immune checkpoint inhibitors in non-small-cell lung cancer."
    supports: SUPPORT
    snippet: A subset of patients who were treated beyond progression with ICI achieved a clinically meaningful response with durable disease control.
    explanation: While it shows the effectiveness of checkpoint inhibitors, it is about treatment beyond progression and does not specifically address high PD-L1 expression.
  - reference: PMID:29140105
    reference_title: "Durvalumab in non-small-cell lung cancer patients: current developments."
    supports: SUPPORT
    snippet: Single-agent durvalumab showed clinical efficacy and a manageable safety profile in advanced non-small-cell lung cancer, particularly the >/=25% PD-L1+ population.
    explanation: This supports the efficacy of durvalumab particularly in PD-L1+ populations but does not specifically mention nivolumab or pembrolizumab.
  - reference: PMID:33306411
    reference_title: "Economic analyses of immune-checkpoint inhibitors to treat lung cancer."
    supports: SUPPORT
    snippet: For the majority of patients, ICIs are cost-effective for lung cancer management.
    explanation: This supports the efficacy of ICIs but does not specifically address tumors with high PD-L1 expression.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
- name: Radiation Therapy
  description: Used for localized disease, palliation of symptoms, or brain metastases
  evidence:
  - reference: PMID:7540125
    reference_title: "New therapeutic strategies involving radiation therapy for patients with non-small cell lung cancer."
    supports: SUPPORT
    snippet: recent notable developments have occurred involving radiation therapy (RT) for patients with non-small cell lung cancer (NSCLC)... For palliation of tumor-related symptoms... metastases to the adrenal gland, liver, and subcutaneous tissues can be palliated successfully by brief courses of RT. Intrathoracic tumor symptoms are well palliated by brief courses of thoracic RT.
    explanation: Supports the use of RT for palliation of symptoms and metastatic sites, but does not specifically mention its use for localized disease.
  - reference: PMID:8853542
    reference_title: "Palliative radiotherapy in Canada."
    supports: SUPPORT
    snippet: In the palliation of non-small cell lung cancer... in the management of chest disease, bone metastases, and brain metastases.
    explanation: Supports the use of RT in palliation of symptoms and brain metastases.
  - reference: PMID:32140986
    reference_title: "Locally Advanced, Unresectable Non-Small Cell Lung Cancer."
    supports: SUPPORT
    snippet: Concurrent chemoradiation is the cornerstone of treatment of unresectable, locally advanced NSCLC.
    explanation: Supports the use of RT for locally advanced (localized) disease.
  - reference: PMID:30441934
    reference_title: "Lung cancer."
    supports: SUPPORT
    snippet: Radiotherapy should also be considered for locally advanced disease.
    explanation: Supports the use of RT for locally advanced (localized) disease.
  - reference: PMID:27467543
    reference_title: "The role of local ablative therapy in oligometastatic non-small-cell lung cancer: hype or hope."
    supports: SUPPORT
    snippet: Stereotactic body radiation therapy has been increasingly used to safely deliver LAT and provide high local control in nonoperable non-small-cell lung cancer patients.
    explanation: Supports the use of RT for localized disease particularly in nonoperable cases.
  therapeutic_modality: RADIOTHERAPY
  treatment_term:
    preferred_term: Radiation Therapy
    term:
      id: NCIT:C15313
      label: Radiation Therapy
- name: Pembrolizumab-Based Immune Checkpoint Therapy
  description: Immune checkpoint inhibitor therapy is a major systemic treatment class in metastatic non-small cell lung cancer, with pembrolizumab-based regimens selected according to PD-L1 expression, tumor genotype, histology, and chemotherapy eligibility.
  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:10.1093/jnci/djae118
    reference_title: Racial and socioeconomic disparities in survival among patients with metastatic non–small cell lung cancer
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Immune checkpoint inhibitors have profoundly impacted survival among patients with metastatic non–small cell lung cancer.
    explanation: Population-level metastatic NSCLC evidence supports immune checkpoint inhibitors as survival-impacting systemic therapy.
experimental_models:
- name: Human orthotopic NSCLC lung organ-on-chip (Wyss Institute)
  description: >-
    Microfluidic human lung organ chip in which non-small-cell lung cancer cells are
    grown within a reconstituted human lung microenvironment under cyclic mechanical
    actuation that mimics breathing motions. A non-animal New Approach Methodology
    that reproduces organ-microenvironment-specific tumour growth, tumour dormancy
    and tyrosine kinase inhibitor responses in vitro, and that resolves the influence
    of physical breathing cues on EGFR and MET signalling.
  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: lung
    term:
      id: UBERON:0002048
      label: lung
  cell_types:
  - preferred_term: lung epithelial cell
    term:
      id: CL:0000082
      label: epithelial cell of lung
  conditions:
  - non-small cell lung carcinoma growth in an orthotopic lung microenvironment
  - tyrosine kinase inhibitor exposure
  - cyclic mechanical strain mimicking breathing motions
  cell_source: >-
    Human non-small-cell lung cancer cells co-cultured with human lung epithelium in a
    reconstituted orthotopic lung microenvironment
  culture_system: >-
    Two-channel microfluidic lung organ chip under continuous perfusion with cyclic
    mechanical actuation reproducing breathing-associated strain
  publication: PMID:29020635
  modeled_mechanisms:
  - target: Oncogenic Driver Mutations
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      The chip reads out driver-kinase-dependent therapeutic response, reproducing the
      tyrosine kinase inhibitor sensitivity seen in patients and resolving EGFR- and
      MET-mediated modulation of that response by the mechanical microenvironment.
    limitations: >-
      Only EGFR and MET signalling were implicated; the ALK and ROS1 rearrangement arms
      of this node were not modelled. The published abstract reports lung cancer cell
      lines in a reconstituted microenvironment rather than patient-derived tumour
      carrying its native driver spectrum, so allele-level genotype-response
      relationships are not established by this system.
    readouts:
    - name: Tyrosine kinase inhibitor therapeutic response
      target: Oncogenic Driver Mutations
      biological_processes:
      - preferred_term: EGFR and MET receptor tyrosine kinase signaling underlying TKI response
        description: >-
          The EGFR and MET signaling changes to which the paper attributes the
          mechanical modulation of TKI response in the chip.
        term:
          id: GO:0007169
          label: cell surface receptor protein tyrosine kinase signaling pathway
      direction: ALTERED
      interpretation: >-
        TKI response in the chip tracked the responses observed in patients, and was
        itself shifted by breathing-like mechanical cues acting through EGFR and MET.
      evidence:
      - reference: PMID:29020635
        reference_title: "Human Organ Chip Models Recapitulate Orthotopic Lung Cancer Growth, Therapeutic Responses, and Tumor Dormancy In Vitro."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: revealed a previously unknown sensitivity of lung cancer cell growth, invasion, and TKI therapeutic responses to physical cues associated with breathing motions, which appear to be mediated by changes in signaling through epidermal growth factor receptor (EGFR) and MET protein kinase
        explanation: >-
          Reports that the chip measured TKI therapeutic response and attributed its
          mechanical modulation to EGFR and MET signalling.
    evidence:
    - reference: PMID:29020635
      reference_title: "Human Organ Chip Models Recapitulate Orthotopic Lung Cancer Growth, Therapeutic Responses, and Tumor Dormancy In Vitro."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: recapitulate organ microenvironment-specific cancer growth, tumor dormancy, and responses to tyrosine kinase inhibitor (TKI) therapy observed in human patients in vivo
      explanation: >-
        Supports treating the chip as informative for driver-kinase-directed therapeutic
        response, since it reproduces the TKI responses observed in patients.
  - target: Tumor Microenvironment Remodeling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The chip reconstitutes an orthotopic lung microenvironment in which tumour growth
      and dormancy are microenvironment-specific, and adds the mechanical dimension of
      breathing motion that static culture cannot supply.
    limitations: >-
      The microenvironment modelled is epithelial and mechanical. The abstract reports no
      immune, myeloid or fibroblast compartment, so the immune-remodelling and
      desmoplastic facets of this node are outside what the system captures.
    readouts:
    - name: Microenvironment-specific tumour growth and dormancy
      target: Tumor Microenvironment Remodeling
      direction: ALTERED
      interpretation: >-
        Growth and entry into dormancy depended on the reconstituted organ
        microenvironment and on breathing-associated mechanical cues.
      evidence:
      - reference: PMID:29020635
        reference_title: "Human Organ Chip Models Recapitulate Orthotopic Lung Cancer Growth, Therapeutic Responses, and Tumor Dormancy In Vitro."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: providing an experimental model to study cancer persister cells and mechanisms of tumor dormancy in vitro
        explanation: >-
          Establishes tumour dormancy and persister-cell behaviour as measurable outputs
          of the reconstituted microenvironment.
    evidence:
    - reference: PMID:29020635
      reference_title: "Human Organ Chip Models Recapitulate Orthotopic Lung Cancer Growth, Therapeutic Responses, and Tumor Dormancy In Vitro."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: recapitulate organ microenvironment-specific cancer growth, tumor dormancy, and responses to tyrosine kinase inhibitor (TKI) therapy observed in human patients in vivo
      explanation: >-
        Supports the claim that tumour behaviour in this system is set by the
        reconstituted organ microenvironment rather than by the tumour cells alone.
  - target: Metastasis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Local invasion of lung cancer cells is measurable in the chip and is sensitive to
      breathing-associated mechanical cues.
    limitations: >-
      Only the local invasive step is represented. The system has no circulation, distant
      organ site, or colonisation compartment, so intravasation, survival in transit and
      metastatic outgrowth - the steps that make this node clinically decisive - are not
      modelled.
    readouts:
    - name: Lung cancer cell invasion under cyclic mechanical strain
      target: Metastasis
      direction: ALTERED
      interpretation: >-
        Invasion was shown to be mechanically sensitive, changing with breathing-like
        actuation rather than being a fixed property of the tumour cells.
      evidence:
      - reference: PMID:29020635
        reference_title: "Human Organ Chip Models Recapitulate Orthotopic Lung Cancer Growth, Therapeutic Responses, and Tumor Dormancy In Vitro."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: revealed a previously unknown sensitivity of lung cancer cell growth, invasion, and TKI therapeutic responses to physical cues associated with breathing motions, which appear to be mediated by changes in signaling through epidermal growth factor receptor (EGFR) and MET protein kinase
        explanation: >-
          Reports invasion as a measured outcome and identifies mechanical cues as a
          determinant of it.
    evidence:
    - reference: PMID:29020635
      reference_title: "Human Organ Chip Models Recapitulate Orthotopic Lung Cancer Growth, Therapeutic Responses, and Tumor Dormancy In Vitro."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: revealed a previously unknown sensitivity of lung cancer cell growth, invasion, and TKI therapeutic responses to physical cues associated with breathing motions
      explanation: >-
        Names invasion as one of the behaviours the chip resolves, which is the local
        invasive step of this node and the only facet of it the system informs.
  notes: >-
    Curated from the NAMeRS 2026 symposium New Approach Methodology tracker
    (monarch-initiative/dismech#4873), Panel 1 organ-chip case study. The underlying
    evidence item was already cited on the Targeted Therapy treatment; this section adds
    the structured model record and its pathograph links.
datasets:
# NSCLC single-cell RNA-seq tumor microenvironment

- accession: geo:GSE131907
  title: Single cell RNA sequencing of lung adenocarcinoma
  description: >-
    Large-scale single-cell RNA sequencing from 11 adjacent normal and
    15 tumor tissue samples from NSCLC patients (stages I-IV). After
    quality filtering, 98,504 cells retained including 16,046 epithelial,
    5,468 stromal, and 76,990 immune cells.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: lung tumor tissue
    tissue_term:
      preferred_term: lung
      term:
        id: UBERON:0002048
        label: lung
  sample_count: 26
  conditions:
  - NSCLC tumor tissue
  - adjacent normal lung tissue
  notes: >-
    Comprehensive single-cell atlas identifying eight major cell types.
    Resolves tumor-infiltrating immune cell heterogeneity relevant to
    immunotherapy response. Part of integrated NSCLC scRNA-seq resource.

# NSCLC single-cell transcriptome heterogeneity

- accession: geo:GSE119911
  title: Comprehensive transcriptomic profiles of non-small cell lung cancer by single-cell RNA-seq
  description: >-
    Single-cell RNA sequencing profiling over 9,000 individual cells
    from tumor and adjacent normal tissues of 20 patients with
    stage I-IV NSCLC using modified STRT-seq technique.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: lung tumor tissue
    tissue_term:
      preferred_term: lung
      term:
        id: UBERON:0002048
        label: lung
  sample_count: 106
  conditions:
  - NSCLC tumor tissue
  - adjacent normal tissue
  notes: >-
    Characterizes inter-patient and intra-tumor heterogeneity including
    epithelial, stromal, and immune cell compartments. Useful for
    understanding cancer progression and therapeutic strategies

# CELLxGENE - Single-cell lung cancer atlas

- accession: "cellxgene:edb893ee-4066-4128-9aec-5eb2b03f8287"
  title: The single-cell lung cancer atlas (LuCA) -- extended atlas
  description: >-
    Comprehensive single-cell lung cancer atlas integrating data across multiple
    NSCLC subtypes and stages. Provides detailed characterization of tumor
    microenvironment cell populations including cancer cells, immune cells, and
    stromal compartments.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: lung tumor tissue
    tissue_term:
      preferred_term: lung
      term:
        id: UBERON:0002048
        label: lung
  conditions:
  - lung adenocarcinoma
  - non-small cell lung carcinoma
  - normal
  publication: PMID:36368568
  notes: CZI CELLxGENE collection. Extended LuCA atlas for tumor microenvironment analysis and virtual cell modeling.

- accession: ega:EGAS50000000105
  title: Efficacy and safety of entrectinib in patients with ROS1-positive advanced/metastatic non-small cell lung cancer (NSCLC) from the Blood First Assay Screening Trial (BFAST)
  description: BFAST is a global, open-label, multicohort trial that evaluates the efficacy and safety of multiple therapies in patients with advanced/metastatic NSCLC and targetable alterations, identified by blood-based molecular testing. We present data from Cohort D (ROS1-positive). Patients ≥18 years old with stage IIIB/IV, ROS1-positive NSCLC detected by blood-based testing, received entrectinib 600 mg daily. At data cut-off (November 2021), 55 patients were enrolled and 54 had measurable disease.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Metastatic Non-Small Cell Lung Cancer"); description-level mentions were not accepted. EGA study_type: Cancer Genomics. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS50000000913
  title: Multi-omic analyses from a randomized phase II study of epigenetic priming followed by nivolumab in previously treated metastatic non-small cell lung cancer
  description: Emergence of resistance to immune checkpoint blockade (ICB) mandates the development of strategies for ICB sensitization. We aimed to understand the effects of epigenetic priming in re-shaping the tumor microenvironment, together with molecular drivers of therapeutic response of epigenetic therapy followed by ICB in non-small cell lung cancer (NSCLC; NCT01928576). This was done through a multi-omic approach encompassing both genomic and transcriptomic analyses. Findings suggest that epigenetic therapy may reshape the tumor microenvironment towards a more inflamed phenotype and prime responses to immunotherapy.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Metastatic Non-Small Cell Lung Cancer"); description-level mentions were not accepted. EGA study_type: Cancer Genomics. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
discussions:
- discussion_id: gap_nsclc_coal_smoke_genomic_phenotype_vs_checkpoint_benefit
  prompt: >-
    Does the coal-smoke-associated genomic phenotype of Xuanwei NSCLC — higher
    tumour mutation burden, predominance of uncommon EGFR alleles, and a
    benzo[a]pyrene mutational signature — actually cause a different benefit
    from PD-1 blockade, or is the reported regional difference in disease
    control rate explained by cohort composition and retrospective design?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Oncogenic Driver Mutations
  - pathophysiology#Immune Evasion
  rationale: >-
    Two claims sit on either side of this gap and nothing yet connects them.
    The genomic side is peer-reviewed and reasonably firm: Xuanwei NSCLC is a
    distinct subtype with significantly higher tumour mutation burden than
    reference Chinese and TCGA cohorts, which is a recognised correlate of
    checkpoint-inhibitor benefit and would predict better response. The
    clinical side is a single-region retrospective real-world comparison,
    available only as a non-peer-reviewed preprint, reporting a higher disease
    control rate for camrelizumab and sintilimab in Xuanwei than non-Xuanwei
    patients — with no accompanying progression-free survival difference, which
    is what a genuine immunobiological advantage would be expected to move.
    Neither study measured TMB and checkpoint-inhibitor outcome in the same
    patients, so the mechanistic bridge is entirely inferred. This entry
    therefore records the question rather than asserting a
    coal-smoke-to-immunotherapy-response edge, and the preprint is deliberately
    not the sole support for anything curated on a node.
  proposed_experiments:
  - experiment_id: exp_nsclc_xuanwei_tmb_stratified_checkpoint_outcome
    name: TMB- and signature-stratified checkpoint-inhibitor outcome cohort in coal-smoke-exposed NSCLC
    description: >-
      Prospectively enrol NSCLC patients receiving PD-1 blockade from
      smoky-coal-exposed and unexposed regions, measure tumour mutation burden,
      SBS4/benzo[a]pyrene-type mutational signature exposure, EGFR allele class,
      and PD-L1 expression on the same tumours, and model objective response,
      disease control rate, and progression-free survival against those
      molecular variables rather than against region of residence.
    experiment_type:
      preferred_term: prospective biomarker-stratified cohort study
    decision_criterion: >-
      The genomic explanation would be supported if checkpoint-inhibitor benefit
      tracked tumour mutation burden or the benzo[a]pyrene signature after
      adjustment, and progression-free survival moved with it. It would be
      undermined if regional origin retained its association once those
      molecular variables and PD-L1 status were accounted for, which would point
      instead to differences in cohort composition, referral, or follow-up.
  evidence:
  - reference: PMID:33889543
    reference_title: "Next-Generation Sequencing Reveals High Uncommon EGFR Mutations and Tumour Mutation Burden in a Subgroup of Lung Cancer Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients from Xuanwei showed a significantly higher tumour mutation burden than the reference Chinese and TCGA cohorts (p < 0.001)."
    explanation: >-
      Establishes the genomic side of the gap — the biomarker that would predict
      differential checkpoint-inhibitor benefit is measurably elevated in this
      population.
  - reference: PMID:39432560
    reference_title: "Proteogenomic analysis of air-pollution-associated lung cancer reveals prevention and therapeutic opportunities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genomic mutation analysis revealed XWLC as a distinct subtype of LUAD separate from cases associated with smoking or endogenous factors."
    explanation: >-
      Supports treating coal-smoke-associated disease as a molecularly distinct
      subtype, which is the premise that makes a differential therapeutic
      response worth testing at all.
  - reference: PPR:PPR1273960
    reference_title: "Efficacy and Safety Analysis of Camrelizumab, Sintilimab, and Tislelizumab in the Treatment of NSCLC in Xuanwei, China: A Retrospective Real-World Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DCR was significantly higher in the Xuanwei group than in the non-Xuanwei group (95.59% vs. 72.88%, P < 0.001)."
    explanation: >-
      The clinical observation that motivates the question. Marked PARTIAL and
      not used to support any pathophysiology node: this is a non-peer-reviewed
      preprint reporting a propensity-matched retrospective comparison of 156
      patients from two hospitals, and the same report finds no between-group
      difference in progression-free survival.
  notes: >-
    Raised from the preprint surfaced in monarch-initiative/dismech#6066. Per
    the preprint-scan policy the PPR reference is cited but is not the sole
    support for any claim, and no mechanism edge was created from it.

disease_term:
  preferred_term: non-small cell lung carcinoma
  term:
    id: MONDO:0005233
    label: non-small cell lung carcinoma

gene_sets:
- gene_set: MYGENESET:KEGG_NON_SMALL_CELL_LUNG_CANCER
  relationship: CANONICAL_PATHWAY
  note: >-
    KEGG non-small cell lung cancer pathway. Metastasis-specific biology is carried by this entry's EMT and Invasion / Brain Metastasis nodes (the former Metastatic_NSCLC entry was folded in).
classifications:
  icdo_morphology:
    classification_value: Carcinoma
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
references:
- reference: DOI:10.1007/s12094-023-03337-9
  title: 'Immunoradiotherapy for NSCLC: mechanisms, clinical outcomes, and future directions'
  findings: []
- reference: DOI:10.1016/j.tips.2024.04.006
  title: 'Immune checkpoint blockade resistance in lung cancer: emerging mechanisms and therapeutic opportunities'
  findings: []
- reference: DOI:10.1038/s41467-024-48700-8
  title: Single-cell and spatial transcriptomics analysis of non-small cell lung cancer
  findings: []
- reference: DOI:10.1038/s41467-024-50157-8
  title: Glucose-6-phosphate dehydrogenase maintains redox homeostasis and biosynthesis in LKB1-deficient KRAS-driven lung cancer
  findings: []
- reference: DOI:10.1038/s41586-024-07943-7
  title: CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors
  findings: []
- reference: DOI:10.1371/journal.pone.0307580
  title: Effects of KRAS, STK11, KEAP1, and TP53 mutations on the clinical outcomes of immune checkpoint inhibitors among patients with lung adenocarcinoma
  findings: []
- reference: DOI:10.3389/fimmu.2024.1439033
  title: 'Potential therapeutic option for EGFR-mutant small cell lung cancer transformation: a case report and literature review'
  findings: []
- reference: DOI:10.3389/fonc.2024.1357583
  title: 'TP53 co-mutations in advanced lung adenocarcinoma: comparative bioinformatic analyses suggest ambivalent character on overall survival alongside KRAS, STK11 and KEAP1 mutations'
  findings: []
- reference: DOI:10.3389/fphar.2023.1125547
  title: Recent progress in targeted therapy for non-small cell lung cancer
  findings: []
- reference: DOI:10.3390/cancers16234048
  title: 'Genetic Blueprints in Lung Cancer: Foundations for Targeted Therapies'
  findings: []
- reference: DOI:10.1016/j.xcrm.2024.101777
  title: Modeling lung adenocarcinoma metastases using patient-derived organoids
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: Modeling lung adenocarcinoma metastases using patient-derived organoids
    supporting_text: Modeling lung adenocarcinoma metastases using patient-derived organoids
- reference: DOI:10.1038/s41392-024-01897-y
  title: 'SHR-A1811 (antibody-drug conjugate) in advanced HER2-mutant non-small cell lung cancer: a multicenter, open-label, phase 1/2 study'
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: A dose-escalation and expansion, phase 1/2 study (ClinicalTrials.gov, NCT04818333) was conducted to assess the novel antibody-drug conjugate SHR-A1811 in pretreated HER2-altered advanced non-small cell lung cancer (NSCLC).
    supporting_text: A dose-escalation and expansion, phase 1/2 study (ClinicalTrials.gov, NCT04818333) was conducted to assess the novel antibody-drug conjugate SHR-A1811 in pretreated HER2-altered advanced non-small cell lung cancer (NSCLC).
    evidence:
    - reference: DOI:10.1038/s41392-024-01897-y
      reference_title: 'SHR-A1811 (antibody-drug conjugate) in advanced HER2-mutant non-small cell lung cancer: a multicenter, open-label, phase 1/2 study'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: A dose-escalation and expansion, phase 1/2 study (ClinicalTrials.gov, NCT04818333) was conducted to assess the novel antibody-drug conjugate SHR-A1811 in pretreated HER2-altered advanced non-small cell lung cancer (NSCLC).
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.1038/s41416-024-02895-1
  title: 'Real-world evidence for pembrolizumab in non-small cell lung cancer: a nationwide cohort study'
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: 'Real-world evidence for pembrolizumab in non-small cell lung cancer: a nationwide cohort study'
    supporting_text: Based on favourable results from clinical trials, immune checkpoint inhibitors (ICI) have become the standard first line (1 L) systemic anticancer treatment (SACT) for advanced stage non-small cell lung cancer (NSCLC) without targetable mutations.
    evidence:
    - reference: DOI:10.1038/s41416-024-02895-1
      reference_title: 'Real-world evidence for pembrolizumab in non-small cell lung cancer: a nationwide cohort study'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Based on favourable results from clinical trials, immune checkpoint inhibitors (ICI) have become the standard first line (1 L) systemic anticancer treatment (SACT) for advanced stage non-small cell lung cancer (NSCLC) without targetable mutations.
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.1038/s41467-024-47547-3
  title: Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: Patient-derived xenograft (PDX) models are widely used in cancer research.
    supporting_text: Patient-derived xenograft (PDX) models are widely used in cancer research.
    evidence:
    - reference: DOI:10.1038/s41467-024-47547-3
      reference_title: Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Patient-derived xenograft (PDX) models are widely used in cancer research.
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.1038/s41598-024-73389-6
  title: Distant metastasis patterns among lung cancer subtypes and impact of primary tumor resection on survival in metastatic lung cancer using SEER database
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: Distant metastasis patterns among lung cancer subtypes and impact of primary tumor resection on survival in metastatic lung cancer using SEER database
    supporting_text: Distant metastasis patterns among lung cancer subtypes and impact of primary tumor resection on survival in metastatic lung cancer using SEER database
- reference: DOI:10.1038/s41698-024-00609-7
  title: Prediction of TKI response in EGFR-mutant lung cancer patients-derived organoids using malignant pleural effusion
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: Patient-derived organoids (PDOs) are valuable in predicting response to cancer therapy.
    supporting_text: Patient-derived organoids (PDOs) are valuable in predicting response to cancer therapy.
    evidence:
    - reference: DOI:10.1038/s41698-024-00609-7
      reference_title: Prediction of TKI response in EGFR-mutant lung cancer patients-derived organoids using malignant pleural effusion
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: Patient-derived organoids (PDOs) are valuable in predicting response to cancer therapy.
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.1056/nejmoa2403614
  title: Amivantamab plus Lazertinib in Previously Untreated <i>EGFR</i> -Mutated Advanced NSCLC
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: Amivantamab plus Lazertinib in Previously Untreated <i>EGFR</i> -Mutated Advanced NSCLC
    supporting_text: Amivantamab plus Lazertinib in Previously Untreated <i>EGFR</i> -Mutated Advanced NSCLC
- reference: DOI:10.1093/jnci/djae118
  title: Racial and socioeconomic disparities in survival among patients with metastatic non–small cell lung cancer
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: Immune checkpoint inhibitors have profoundly impacted survival among patients with metastatic non–small cell lung cancer.
    supporting_text: Immune checkpoint inhibitors have profoundly impacted survival among patients with metastatic non–small cell lung cancer.
    evidence:
    - reference: DOI:10.1093/jnci/djae118
      reference_title: Racial and socioeconomic disparities in survival among patients with metastatic non–small cell lung cancer
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Immune checkpoint inhibitors have profoundly impacted survival among patients with metastatic non–small cell lung cancer.
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.1177/17588359241231260
  title: 'Geographic differences in lung cancer: focus on carcinogens, genetic predisposition, and molecular epidemiology'
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: Lung cancer poses a global health challenge and stands as the leading cause of cancer-related deaths worldwide.
    supporting_text: Lung cancer poses a global health challenge and stands as the leading cause of cancer-related deaths worldwide.
    evidence:
    - reference: DOI:10.1177/17588359241231260
      reference_title: 'Geographic differences in lung cancer: focus on carcinogens, genetic predisposition, and molecular epidemiology'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Lung cancer poses a global health challenge and stands as the leading cause of cancer-related deaths worldwide.
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.1177/17588359241303090
  title: 'Femoral bone metastasis is a poor prognostic factor in EGFR-TKIs-treated patients with <i>EGFR</i> -mutated non-small-cell lung cancer: a retrospective, multicenter cohort study'
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: Epidermal growth factor receptor ( EGFR)-mutant non-small-cell lung cancers (NSCLCs) have higher frequencies of bone metastases than those of wild type; however, the metastatic pattern and influence on clinical outcome remain unclear.
    supporting_text: Epidermal growth factor receptor ( EGFR)-mutant non-small-cell lung cancers (NSCLCs) have higher frequencies of bone metastases than those of wild type; however, the metastatic pattern and influence on clinical outcome remain unclear.
    evidence:
    - reference: DOI:10.1177/17588359241303090
      reference_title: 'Femoral bone metastasis is a poor prognostic factor in EGFR-TKIs-treated patients with <i>EGFR</i> -mutated non-small-cell lung cancer: a retrospective, multicenter cohort study'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Epidermal growth factor receptor ( EGFR)-mutant non-small-cell lung cancers (NSCLCs) have higher frequencies of bone metastases than those of wild type; however, the metastatic pattern and influence on clinical outcome remain unclear.
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.1186/s10020-024-00934-4
  title: Utility of patient-derived xenografts to evaluate drug sensitivity and select optimal treatments for individual non-small-cell lung cancer patients
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: Patient-derived xenograft (PDX) is currently considered a preferred preclinical model to evaluate drug sensitivity, explore drug resistance mechanisms, and select individualized treatment regimens.
    supporting_text: Patient-derived xenograft (PDX) is currently considered a preferred preclinical model to evaluate drug sensitivity, explore drug resistance mechanisms, and select individualized treatment regimens.
    evidence:
    - reference: DOI:10.1186/s10020-024-00934-4
      reference_title: Utility of patient-derived xenografts to evaluate drug sensitivity and select optimal treatments for individual non-small-cell lung cancer patients
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Patient-derived xenograft (PDX) is currently considered a preferred preclinical model to evaluate drug sensitivity, explore drug resistance mechanisms, and select individualized treatment regimens.
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.1186/s12957-024-03449-8
  title: 'Efficacy and toxicity of KRASG12C inhibitors in advanced solid tumors: a meta-analysis'
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: The efficacy and toxicity of KRASG12C inhibitors were evaluated for advanced solid tumors in several studies; however, the results were not fully consistent.
    supporting_text: The efficacy and toxicity of KRASG12C inhibitors were evaluated for advanced solid tumors in several studies; however, the results were not fully consistent.
    evidence:
    - reference: DOI:10.1186/s12957-024-03449-8
      reference_title: 'Efficacy and toxicity of KRASG12C inhibitors in advanced solid tumors: a meta-analysis'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The efficacy and toxicity of KRASG12C inhibitors were evaluated for advanced solid tumors in several studies; however, the results were not fully consistent.
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.1200/oa.24.00008
  title: 'Disparities in Utilization of Immune Checkpoint Inhibitor Therapy Among Older Patients With Advanced Non–Small Cell Lung Cancer: A SEER-Medicare Analysis'
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: In the United States, there are disparities in access to care for patients with non–small cell lung cancer (NSCLC) on the basis of socioeconomic and racial/ethnic factors.
    supporting_text: In the United States, there are disparities in access to care for patients with non–small cell lung cancer (NSCLC) on the basis of socioeconomic and racial/ethnic factors.
    evidence:
    - reference: DOI:10.1200/oa.24.00008
      reference_title: 'Disparities in Utilization of Immune Checkpoint Inhibitor Therapy Among Older Patients With Advanced Non–Small Cell Lung Cancer: A SEER-Medicare Analysis'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In the United States, there are disparities in access to care for patients with non–small cell lung cancer (NSCLC) on the basis of socioeconomic and racial/ethnic factors.
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.18502/jhsw.v14i1.17131
  title: 'Investigating the Relationship Between Exposure to Cadmium and Lung Cancer Risk: A Systematic Review and Meta-analysis'
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: Lung cancer is the second most common cancer in the world.
    supporting_text: Lung cancer is the second most common cancer in the world.
    evidence:
    - reference: DOI:10.18502/jhsw.v14i1.17131
      reference_title: 'Investigating the Relationship Between Exposure to Cadmium and Lung Cancer Risk: A Systematic Review and Meta-analysis'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Lung cancer is the second most common cancer in the world.
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.21037/tlcr-24-856
  title: A potential central nervous system niche for trastuzumab deruxtecan in patients with HER2-expressing non-small cell lung cancer
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: A potential central nervous system niche for trastuzumab deruxtecan in patients with HER2-expressing non-small cell lung cancer
    supporting_text: A potential central nervous system niche for trastuzumab deruxtecan in patients with HER2-expressing non-small cell lung cancer
- reference: DOI:10.2147/dddt.s466217
  title: 'Adagrasib in the Treatment of KRAS p.G12C Positive Advanced NSCLC: Design, Development and Place in Therapy'
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: 'Adagrasib in the Treatment of KRAS p.G12C Positive Advanced NSCLC: Design, Development and Place in Therapy'
    supporting_text: 'Adagrasib in the Treatment of KRAS p.G12C Positive Advanced NSCLC: Design, Development and Place in Therapy'
- reference: DOI:10.3322/caac.21811
  title: 'Screening for lung cancer: 2023 guideline update from the American Cancer Society'
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: Lung cancer is the leading cause of mortality and person‐years of life lost from cancer among US men and women.
    supporting_text: Lung cancer is the leading cause of mortality and person‐years of life lost from cancer among US men and women.
    evidence:
    - reference: DOI:10.3322/caac.21811
      reference_title: 'Screening for lung cancer: 2023 guideline update from the American Cancer Society'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Lung cancer is the leading cause of mortality and person‐years of life lost from cancer among US men and women.
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.3389/fonc.2023.1241402
  title: 'Non-small cell lung cancer with MET amplification: review of epidemiology, associated disease characteristics, testing procedures, burden, and treatments'
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: Mesenchymal-epidermal transition factor gene amplification (METamp) is being investigated as a therapeutic target in advanced non-small cell lung cancer (NSCLC).
    supporting_text: Mesenchymal-epidermal transition factor gene amplification (METamp) is being investigated as a therapeutic target in advanced non-small cell lung cancer (NSCLC).
    evidence:
    - reference: DOI:10.3389/fonc.2023.1241402
      reference_title: 'Non-small cell lung cancer with MET amplification: review of epidemiology, associated disease characteristics, testing procedures, burden, and treatments'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Mesenchymal-epidermal transition factor gene amplification (METamp) is being investigated as a therapeutic target in advanced non-small cell lung cancer (NSCLC).
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.3389/fonc.2024.1328728
  title: Mechanisms of resistance to KRASG12C inhibitors in KRASG12C-mutated non-small cell lung cancer
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: The KRAS protein, a product of the KRAS gene (V-ki-ras2 Kirsten rat sarcoma viral oncogene homolog), functions as a small GTPase that alternates between an active GTP-bound state (KRAS(ON)) and an inactive GDP-bound state (KRAS(OFF)).
    supporting_text: The KRAS protein, a product of the KRAS gene (V-ki-ras2 Kirsten rat sarcoma viral oncogene homolog), functions as a small GTPase that alternates between an active GTP-bound state (KRAS(ON)) and an inactive GDP-bound state (KRAS(OFF)).
    evidence:
    - reference: DOI:10.3389/fonc.2024.1328728
      reference_title: Mechanisms of resistance to KRASG12C inhibitors in KRASG12C-mutated non-small cell lung cancer
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The KRAS protein, a product of the KRAS gene (V-ki-ras2 Kirsten rat sarcoma viral oncogene homolog), functions as a small GTPase that alternates between an active GTP-bound state (KRAS(ON)) and an inactive GDP-bound state (KRAS(OFF)).
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.3389/fonc.2024.1442909
  title: Real-world treatment patterns, biomarker testing, and clinical outcomes of metastatic non-small cell lung cancer patients in the immunotherapy era
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: Treatment for first-line (1L) metastatic non-small cell cancer (mNSCLC) changed with the introduction of immunotherapy.
    supporting_text: Treatment for first-line (1L) metastatic non-small cell cancer (mNSCLC) changed with the introduction of immunotherapy.
    evidence:
    - reference: DOI:10.3389/fonc.2024.1442909
      reference_title: Real-world treatment patterns, biomarker testing, and clinical outcomes of metastatic non-small cell lung cancer patients in the immunotherapy era
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Treatment for first-line (1L) metastatic non-small cell cancer (mNSCLC) changed with the introduction of immunotherapy.
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.3390/cancers16112018
  title: 'HER2-Altered Non-Small Cell Lung Cancer: A Journey from Current Approaches to Emerging Strategies'
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: For patients diagnosed with advanced HER2-altered non-small cell lung cancer (NSCLC), the current standard of care is represented by a platinum-pemetrexed-based chemotherapy, eventually in combination with immunotherapy.
    supporting_text: For patients diagnosed with advanced HER2-altered non-small cell lung cancer (NSCLC), the current standard of care is represented by a platinum-pemetrexed-based chemotherapy, eventually in combination with immunotherapy.
    evidence:
    - reference: DOI:10.3390/cancers16112018
      reference_title: 'HER2-Altered Non-Small Cell Lung Cancer: A Journey from Current Approaches to Emerging Strategies'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: For patients diagnosed with advanced HER2-altered non-small cell lung cancer (NSCLC), the current standard of care is represented by a platinum-pemetrexed-based chemotherapy, eventually in combination with immunotherapy.
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.3390/cancers16112136
  title: Site-Specific Response and Resistance Patterns in Patients with Advanced Non-Small-Cell Lung Cancer Treated with First-Line Systemic Therapy
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: Patients with advanced NSCLC have heterogenous responses to immune checkpoint inhibitors (ICIs) with or without chemotherapy.
    supporting_text: Patients with advanced NSCLC have heterogenous responses to immune checkpoint inhibitors (ICIs) with or without chemotherapy.
    evidence:
    - reference: DOI:10.3390/cancers16112136
      reference_title: Site-Specific Response and Resistance Patterns in Patients with Advanced Non-Small-Cell Lung Cancer Treated with First-Line Systemic Therapy
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Patients with advanced NSCLC have heterogenous responses to immune checkpoint inhibitors (ICIs) with or without chemotherapy.
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.3390/cancers16132338
  title: 'Identification and Application of Emerging Biomarkers in Treatment of Non-Small-Cell Lung Cancer: Systematic Review'
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: Non-small-cell lung cancer (NSCLC) comprises approximately 85% of all lung cancer cases, often diagnosed at advanced stages, which diminishes the effective treatment options and survival rates.
    supporting_text: Non-small-cell lung cancer (NSCLC) comprises approximately 85% of all lung cancer cases, often diagnosed at advanced stages, which diminishes the effective treatment options and survival rates.
    evidence:
    - reference: DOI:10.3390/cancers16132338
      reference_title: 'Identification and Application of Emerging Biomarkers in Treatment of Non-Small-Cell Lung Cancer: Systematic Review'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Non-small-cell lung cancer (NSCLC) comprises approximately 85% of all lung cancer cases, often diagnosed at advanced stages, which diminishes the effective treatment options and survival rates.
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.3390/cancers16132350
  title: Evolving Precision First-Line Systemic Treatment for Patients with Unresectable Non-Small Cell Lung Cancer
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: First-line systemic therapy for patients with advanced or metastatic non-small cell lung cancer (NSCLC) has rapidly evolved over the past two decades.
    supporting_text: First-line systemic therapy for patients with advanced or metastatic non-small cell lung cancer (NSCLC) has rapidly evolved over the past two decades.
    evidence:
    - reference: DOI:10.3390/cancers16132350
      reference_title: Evolving Precision First-Line Systemic Treatment for Patients with Unresectable Non-Small Cell Lung Cancer
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: First-line systemic therapy for patients with advanced or metastatic non-small cell lung cancer (NSCLC) has rapidly evolved over the past two decades.
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.37349/etat.2024.00277
  title: Addressing the unmet need in NSCLC progression with advances in second-line therapeutics
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: Lung cancer is the leading cause of cancer mortality globally, with non-small cell lung cancer (NSCLC) accounting for 85% of cases.
    supporting_text: Lung cancer is the leading cause of cancer mortality globally, with non-small cell lung cancer (NSCLC) accounting for 85% of cases.
    evidence:
    - reference: DOI:10.37349/etat.2024.00277
      reference_title: Addressing the unmet need in NSCLC progression with advances in second-line therapeutics
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Lung cancer is the leading cause of cancer mortality globally, with non-small cell lung cancer (NSCLC) accounting for 85% of cases.
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.
- reference: DOI:10.4046/trd.2024.0092
  title: Update in Association between Lung Cancer and Air Pollution
  found_in:
  - Metastatic_NSCLC-deep-research-falcon.md
  findings:
  - statement: A significant portion of newly diagnosed lung cancer cases occurs in populations exposed to air pollution.
    supporting_text: A significant portion of newly diagnosed lung cancer cases occurs in populations exposed to air pollution.
    evidence:
    - reference: DOI:10.4046/trd.2024.0092
      reference_title: Update in Association between Lung Cancer and Air Pollution
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: A significant portion of newly diagnosed lung cancer cases occurs in populations exposed to air pollution.
      explanation: Deep research cited this publication as relevant literature for Metastatic NSCLC.

📚

References & Deep Research

References

DOI:10.1007/s12094-023-03337-9

Immunoradiotherapy for NSCLC: mechanisms, clinical outcomes, and future directions

No top-level findings curated for this source.

DOI:10.1016/j.tips.2024.04.006

Immune checkpoint blockade resistance in lung cancer: emerging mechanisms and therapeutic opportunities

No top-level findings curated for this source.

DOI:10.1038/s41467-024-48700-8

Single-cell and spatial transcriptomics analysis of non-small cell lung cancer

No top-level findings curated for this source.

DOI:10.1038/s41467-024-50157-8

Glucose-6-phosphate dehydrogenase maintains redox homeostasis and biosynthesis in LKB1-deficient KRAS-driven lung cancer

No top-level findings curated for this source.

DOI:10.1038/s41586-024-07943-7

CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors

No top-level findings curated for this source.

DOI:10.1371/journal.pone.0307580

Effects of KRAS, STK11, KEAP1, and TP53 mutations on the clinical outcomes of immune checkpoint inhibitors among patients with lung adenocarcinoma

No top-level findings curated for this source.

DOI:10.3389/fimmu.2024.1439033

Potential therapeutic option for EGFR-mutant small cell lung cancer transformation: a case report and literature review

No top-level findings curated for this source.

DOI:10.3389/fonc.2024.1357583

TP53 co-mutations in advanced lung adenocarcinoma: comparative bioinformatic analyses suggest ambivalent character on overall survival alongside KRAS, STK11 and KEAP1 mutations

No top-level findings curated for this source.

DOI:10.3389/fphar.2023.1125547

Recent progress in targeted therapy for non-small cell lung cancer

No top-level findings curated for this source.

DOI:10.3390/cancers16234048

Genetic Blueprints in Lung Cancer: Foundations for Targeted Therapies

No top-level findings curated for this source.

DOI:10.1016/j.xcrm.2024.101777

Modeling lung adenocarcinoma metastases using patient-derived organoids

1 finding

Modeling lung adenocarcinoma metastases using patient-derived organoids

"Modeling lung adenocarcinoma metastases using patient-derived organoids"

DOI:10.1038/s41392-024-01897-y

SHR-A1811 (antibody-drug conjugate) in advanced HER2-mutant non-small cell lung cancer: a multicenter, open-label, phase 1/2 study

1 finding

A dose-escalation and expansion, phase 1/2 study (ClinicalTrials.gov, NCT04818333) was conducted to assess the novel antibody-drug conjugate SHR-A1811 in pretreated HER2-altered advanced non-small cell lung cancer (NSCLC).

"A dose-escalation and expansion, phase 1/2 study (ClinicalTrials.gov, NCT04818333) was conducted to assess the novel antibody-drug conjugate SHR-A1811 in pretreated HER2-altered advanced non-small cell lung cancer (NSCLC)."

Show evidence (1 reference)

DOI:10.1038/s41392-024-01897-y SUPPORT Human Clinical

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.1038/s41416-024-02895-1

Real-world evidence for pembrolizumab in non-small cell lung cancer: a nationwide cohort study

1 finding

Real-world evidence for pembrolizumab in non-small cell lung cancer: a nationwide cohort study

"Based on favourable results from clinical trials, immune checkpoint inhibitors (ICI) have become the standard first line (1 L) systemic anticancer treatment (SACT) for advanced stage non-small cell lung cancer (NSCLC) without targetable mutations."

Show evidence (1 reference)

DOI:10.1038/s41416-024-02895-1 SUPPORT Human Clinical

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.1038/s41467-024-47547-3

Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models

1 finding

Patient-derived xenograft (PDX) models are widely used in cancer research.

"Patient-derived xenograft (PDX) models are widely used in cancer research."

Show evidence (1 reference)

DOI:10.1038/s41467-024-47547-3 SUPPORT Human Clinical

"Patient-derived xenograft (PDX) models are widely used in cancer research."

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.1038/s41598-024-73389-6

Distant metastasis patterns among lung cancer subtypes and impact of primary tumor resection on survival in metastatic lung cancer using SEER database

1 finding

Distant metastasis patterns among lung cancer subtypes and impact of primary tumor resection on survival in metastatic lung cancer using SEER database

"Distant metastasis patterns among lung cancer subtypes and impact of primary tumor resection on survival in metastatic lung cancer using SEER database"

DOI:10.1038/s41698-024-00609-7

Prediction of TKI response in EGFR-mutant lung cancer patients-derived organoids using malignant pleural effusion

1 finding

Patient-derived organoids (PDOs) are valuable in predicting response to cancer therapy.

"Patient-derived organoids (PDOs) are valuable in predicting response to cancer therapy."

Show evidence (1 reference)

DOI:10.1038/s41698-024-00609-7 SUPPORT Computational

"Patient-derived organoids (PDOs) are valuable in predicting response to cancer therapy."

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.1056/nejmoa2403614

Amivantamab plus Lazertinib in Previously Untreated EGFR -Mutated Advanced NSCLC

1 finding

Amivantamab plus Lazertinib in Previously Untreated EGFR -Mutated Advanced NSCLC

"Amivantamab plus Lazertinib in Previously Untreated EGFR -Mutated Advanced NSCLC"

DOI:10.1093/jnci/djae118

Racial and socioeconomic disparities in survival among patients with metastatic non–small cell lung cancer

1 finding

Immune checkpoint inhibitors have profoundly impacted survival among patients with metastatic non–small cell lung cancer.

"Immune checkpoint inhibitors have profoundly impacted survival among patients with metastatic non–small cell lung cancer."

Show evidence (1 reference)

DOI:10.1093/jnci/djae118 SUPPORT Human Clinical

"Immune checkpoint inhibitors have profoundly impacted survival among patients with metastatic non–small cell lung cancer."

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.1177/17588359241231260

Geographic differences in lung cancer: focus on carcinogens, genetic predisposition, and molecular epidemiology

1 finding

Lung cancer poses a global health challenge and stands as the leading cause of cancer-related deaths worldwide.

"Lung cancer poses a global health challenge and stands as the leading cause of cancer-related deaths worldwide."

Show evidence (1 reference)

DOI:10.1177/17588359241231260 SUPPORT Human Clinical

"Lung cancer poses a global health challenge and stands as the leading cause of cancer-related deaths worldwide."

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.1177/17588359241303090

Femoral bone metastasis is a poor prognostic factor in EGFR-TKIs-treated patients with EGFR -mutated non-small-cell lung cancer: a retrospective, multicenter cohort study

1 finding

Epidermal growth factor receptor ( EGFR)-mutant non-small-cell lung cancers (NSCLCs) have higher frequencies of bone metastases than those of wild type; however, the metastatic pattern and influence on clinical outcome remain unclear.

"Epidermal growth factor receptor ( EGFR)-mutant non-small-cell lung cancers (NSCLCs) have higher frequencies of bone metastases than those of wild type; however, the metastatic pattern and influence on clinical outcome remain unclear."

Show evidence (1 reference)

DOI:10.1177/17588359241303090 SUPPORT Human Clinical

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.1186/s10020-024-00934-4

Utility of patient-derived xenografts to evaluate drug sensitivity and select optimal treatments for individual non-small-cell lung cancer patients

1 finding

Patient-derived xenograft (PDX) is currently considered a preferred preclinical model to evaluate drug sensitivity, explore drug resistance mechanisms, and select individualized treatment regimens.

"Patient-derived xenograft (PDX) is currently considered a preferred preclinical model to evaluate drug sensitivity, explore drug resistance mechanisms, and select individualized treatment regimens."

Show evidence (1 reference)

DOI:10.1186/s10020-024-00934-4 SUPPORT Human Clinical

"Patient-derived xenograft (PDX) is currently considered a preferred preclinical model to evaluate drug sensitivity, explore drug resistance mechanisms, and select individualized treatment regimens."

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.1186/s12957-024-03449-8

Efficacy and toxicity of KRASG12C inhibitors in advanced solid tumors: a meta-analysis

1 finding

The efficacy and toxicity of KRASG12C inhibitors were evaluated for advanced solid tumors in several studies; however, the results were not fully consistent.

"The efficacy and toxicity of KRASG12C inhibitors were evaluated for advanced solid tumors in several studies; however, the results were not fully consistent."

Show evidence (1 reference)

DOI:10.1186/s12957-024-03449-8 SUPPORT Other

"The efficacy and toxicity of KRASG12C inhibitors were evaluated for advanced solid tumors in several studies; however, the results were not fully consistent."

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.1200/oa.24.00008

Disparities in Utilization of Immune Checkpoint Inhibitor Therapy Among Older Patients With Advanced Non–Small Cell Lung Cancer: A SEER-Medicare Analysis

1 finding

In the United States, there are disparities in access to care for patients with non–small cell lung cancer (NSCLC) on the basis of socioeconomic and racial/ethnic factors.

"In the United States, there are disparities in access to care for patients with non–small cell lung cancer (NSCLC) on the basis of socioeconomic and racial/ethnic factors."

Show evidence (1 reference)

DOI:10.1200/oa.24.00008 SUPPORT Human Clinical

"In the United States, there are disparities in access to care for patients with non–small cell lung cancer (NSCLC) on the basis of socioeconomic and racial/ethnic factors."

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.18502/jhsw.v14i1.17131

Investigating the Relationship Between Exposure to Cadmium and Lung Cancer Risk: A Systematic Review and Meta-analysis

1 finding

Lung cancer is the second most common cancer in the world.

"Lung cancer is the second most common cancer in the world."

Show evidence (1 reference)

DOI:10.18502/jhsw.v14i1.17131 SUPPORT Other

"Lung cancer is the second most common cancer in the world."

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.21037/tlcr-24-856

A potential central nervous system niche for trastuzumab deruxtecan in patients with HER2-expressing non-small cell lung cancer

1 finding

A potential central nervous system niche for trastuzumab deruxtecan in patients with HER2-expressing non-small cell lung cancer

"A potential central nervous system niche for trastuzumab deruxtecan in patients with HER2-expressing non-small cell lung cancer"

DOI:10.2147/dddt.s466217

Adagrasib in the Treatment of KRAS p.G12C Positive Advanced NSCLC: Design, Development and Place in Therapy

1 finding

Adagrasib in the Treatment of KRAS p.G12C Positive Advanced NSCLC: Design, Development and Place in Therapy

"Adagrasib in the Treatment of KRAS p.G12C Positive Advanced NSCLC: Design, Development and Place in Therapy"

DOI:10.3322/caac.21811

Screening for lung cancer: 2023 guideline update from the American Cancer Society

1 finding

Lung cancer is the leading cause of mortality and person‐years of life lost from cancer among US men and women.

"Lung cancer is the leading cause of mortality and person‐years of life lost from cancer among US men and women."

Show evidence (1 reference)

DOI:10.3322/caac.21811 SUPPORT Other

"Lung cancer is the leading cause of mortality and person‐years of life lost from cancer among US men and women."

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.3389/fonc.2023.1241402

Non-small cell lung cancer with MET amplification: review of epidemiology, associated disease characteristics, testing procedures, burden, and treatments

1 finding

Mesenchymal-epidermal transition factor gene amplification (METamp) is being investigated as a therapeutic target in advanced non-small cell lung cancer (NSCLC).

"Mesenchymal-epidermal transition factor gene amplification (METamp) is being investigated as a therapeutic target in advanced non-small cell lung cancer (NSCLC)."

Show evidence (1 reference)

DOI:10.3389/fonc.2023.1241402 SUPPORT Human Clinical

"Mesenchymal-epidermal transition factor gene amplification (METamp) is being investigated as a therapeutic target in advanced non-small cell lung cancer (NSCLC)."

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.3389/fonc.2024.1328728

Mechanisms of resistance to KRASG12C inhibitors in KRASG12C-mutated non-small cell lung cancer

1 finding

The KRAS protein, a product of the KRAS gene (V-ki-ras2 Kirsten rat sarcoma viral oncogene homolog), functions as a small GTPase that alternates between an active GTP-bound state (KRAS(ON)) and an inactive GDP-bound state (KRAS(OFF)).

"The KRAS protein, a product of the KRAS gene (V-ki-ras2 Kirsten rat sarcoma viral oncogene homolog), functions as a small GTPase that alternates between an active GTP-bound state (KRAS(ON)) and an inactive GDP-bound state (KRAS(OFF))."

Show evidence (1 reference)

DOI:10.3389/fonc.2024.1328728 SUPPORT Human Clinical

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.3389/fonc.2024.1442909

Real-world treatment patterns, biomarker testing, and clinical outcomes of metastatic non-small cell lung cancer patients in the immunotherapy era

1 finding

Treatment for first-line (1L) metastatic non-small cell cancer (mNSCLC) changed with the introduction of immunotherapy.

"Treatment for first-line (1L) metastatic non-small cell cancer (mNSCLC) changed with the introduction of immunotherapy."

Show evidence (1 reference)

DOI:10.3389/fonc.2024.1442909 SUPPORT Human Clinical

"Treatment for first-line (1L) metastatic non-small cell cancer (mNSCLC) changed with the introduction of immunotherapy."

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.3390/cancers16112018

HER2-Altered Non-Small Cell Lung Cancer: A Journey from Current Approaches to Emerging Strategies

1 finding

For patients diagnosed with advanced HER2-altered non-small cell lung cancer (NSCLC), the current standard of care is represented by a platinum-pemetrexed-based chemotherapy, eventually in combination with immunotherapy.

"For patients diagnosed with advanced HER2-altered non-small cell lung cancer (NSCLC), the current standard of care is represented by a platinum-pemetrexed-based chemotherapy, eventually in combination with immunotherapy."

Show evidence (1 reference)

DOI:10.3390/cancers16112018 SUPPORT Human Clinical

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.3390/cancers16112136

Site-Specific Response and Resistance Patterns in Patients with Advanced Non-Small-Cell Lung Cancer Treated with First-Line Systemic Therapy

1 finding

Patients with advanced NSCLC have heterogenous responses to immune checkpoint inhibitors (ICIs) with or without chemotherapy.

"Patients with advanced NSCLC have heterogenous responses to immune checkpoint inhibitors (ICIs) with or without chemotherapy."

Show evidence (1 reference)

DOI:10.3390/cancers16112136 SUPPORT Human Clinical

"Patients with advanced NSCLC have heterogenous responses to immune checkpoint inhibitors (ICIs) with or without chemotherapy."

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.3390/cancers16132338

Identification and Application of Emerging Biomarkers in Treatment of Non-Small-Cell Lung Cancer: Systematic Review

1 finding

Non-small-cell lung cancer (NSCLC) comprises approximately 85% of all lung cancer cases, often diagnosed at advanced stages, which diminishes the effective treatment options and survival rates.

"Non-small-cell lung cancer (NSCLC) comprises approximately 85% of all lung cancer cases, often diagnosed at advanced stages, which diminishes the effective treatment options and survival rates."

Show evidence (1 reference)

DOI:10.3390/cancers16132338 SUPPORT Other

"Non-small-cell lung cancer (NSCLC) comprises approximately 85% of all lung cancer cases, often diagnosed at advanced stages, which diminishes the effective treatment options and survival rates."

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.3390/cancers16132350

Evolving Precision First-Line Systemic Treatment for Patients with Unresectable Non-Small Cell Lung Cancer

1 finding

First-line systemic therapy for patients with advanced or metastatic non-small cell lung cancer (NSCLC) has rapidly evolved over the past two decades.

"First-line systemic therapy for patients with advanced or metastatic non-small cell lung cancer (NSCLC) has rapidly evolved over the past two decades."

Show evidence (1 reference)

DOI:10.3390/cancers16132350 SUPPORT Computational

"First-line systemic therapy for patients with advanced or metastatic non-small cell lung cancer (NSCLC) has rapidly evolved over the past two decades."

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.37349/etat.2024.00277

Addressing the unmet need in NSCLC progression with advances in second-line therapeutics

1 finding

Lung cancer is the leading cause of cancer mortality globally, with non-small cell lung cancer (NSCLC) accounting for 85% of cases.

"Lung cancer is the leading cause of cancer mortality globally, with non-small cell lung cancer (NSCLC) accounting for 85% of cases."

Show evidence (1 reference)

DOI:10.37349/etat.2024.00277 SUPPORT Human Clinical

"Lung cancer is the leading cause of cancer mortality globally, with non-small cell lung cancer (NSCLC) accounting for 85% of cases."

Deep research cited this publication as relevant literature for Metastatic NSCLC.

DOI:10.4046/trd.2024.0092

Update in Association between Lung Cancer and Air Pollution

1 finding

A significant portion of newly diagnosed lung cancer cases occurs in populations exposed to air pollution.

"A significant portion of newly diagnosed lung cancer cases occurs in populations exposed to air pollution."

Show evidence (1 reference)

DOI:10.4046/trd.2024.0092 SUPPORT Human Clinical

"A significant portion of newly diagnosed lung cancer cases occurs in populations exposed to air pollution."

Deep research cited this publication as relevant literature for Metastatic NSCLC.

Deep Research

Disorder ▸

Disorder

Name: Non-Small Cell Lung Cancer
Category:
Existing deep-research providers: falcon
Existing evidence reference count in YAML: 126

Key Pathophysiology Nodes

Oncogenic Driver Mutations
Immune Evasion
Angiogenesis
Tumor Microenvironment Remodeling
Metabolic Rewiring
Metastasis
Deep research literature mapping

Citation Inventory (for evidence mapping)

DOI:10.1007/s12094-023-03337-9
DOI:10.1016/j.tips.2024.04.006
DOI:10.1038/s41467-024-48700-8
DOI:10.1038/s41467-024-50157-8
DOI:10.1038/s41586-024-07943-7
DOI:10.1371/journal.pone.0307580
DOI:10.3389/fimmu.2024.1439033
DOI:10.3389/fonc.2024.1357583
DOI:10.3389/fphar.2023.1125547
DOI:10.3390/cancers16234048

Falcon ▸

Disease Pathophysiology Research Report

Edison Scientific Literature 25 citations 2025-12-15T09:11:27.074723

Disease Pathophysiology Research Report

Target Disease - Disease Name: Non-Small Cell Lung Cancer (NSCLC) - MONDO ID: MONDO:0005233 - Category: Malignant neoplasm of lung (thoracic oncology)

Pathophysiology description (current understanding) NSCLC progression is driven by oncogenic signaling (EGFR, KRAS, ALK, MET) and tumor suppressor loss (TP53, STK11/LKB1, KEAP1/NFE2L2), which remodel tumor-cell intrinsic programs and the tumor microenvironment (TME) to enable immune evasion, metastasis, therapy resistance, and metabolic rewiring. High-resolution single-cell and spatial atlases demonstrate macrophage-dominant, immunosuppressive niches with reduced NK/T-cell cytotoxicity, and transcriptional reprogramming of tumor-associated macrophages (TAMs) toward cholesterol export/iron efflux states within tumors (Nature Communications, 2024) (zuani2024singlecellandspatial pages 1-2). Co-mutation patterns (e.g., KRAS with STK11 and/or KEAP1) are repeatedly associated with “cold” TMEs and inferior outcomes on immune checkpoint inhibitors (ICIs), whereas dual PD-(L)1/CTLA-4 blockade can partially overcome KEAP1/STK11-related resistance (Nature, 2024) (liang2024effectsofkras pages 1-2, konen2024immunecheckpointblockade pages 14-16). Metabolically, KRAS/LKB1 (KL) tumors exhibit dependency on oxidative pentose phosphate pathway (PPP) NADPH production via G6PD; genetic ablation of G6PD selectively suppresses KL tumorigenesis and activates p53, indicating a therapeutically exploitable redox vulnerability (Nature Communications, 2024) (zuani2024singlecellandspatial pages 1-2).

Key concepts and definitions with curated quotes - Tumor microenvironment remodeling at single-cell resolution: “We profile approximately 900,000 cells… We note an inverse relationship between anti-inflammatory macrophages and NK cells/T cells… macrophages… shifting them towards cholesterol export and adopting a foetal-like transcriptional signature which promotes iron efflux.” (Nature Communications, 2024; URL: https://doi.org/10.1038/s41467-024-48700-8; published May 2024) (zuani2024singlecellandspatial pages 1-2) - Dual ICI in KEAP1/STK11-altered NSCLC: “Patients with NSCLC who have mutations in the STK11 and/or KEAP1… derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone…” (Nature, 2024; URL: https://doi.org/10.1038/s41586-024-07943-7; Oct 2024) (liang2024effectsofkras pages 1-2) - G6PD metabolic dependency in KL tumors: “G6PD ablation significantly suppresses KrasG12D/+;Lkb1−/− (KL) but not KrasG12D/+;P53−/− (KP) lung tumorigenesis… impairs NADPH generation, redox balance, and de novo lipogenesis in KL… activates p53.” (Nature Communications, 2024; URL: https://doi.org/10.1038/s41467-024-50157-8; Jul 2024) (zuani2024singlecellandspatial pages 1-2) - Clinical impact of STK11/KEAP1/TP53 on ICI outcomes: Among 343 LUAD patients treated with ICIs, “KEAP1 (HR = 1.890, P = 0.008) and TP53 (HR = 1.735, P = 0.011) mutations were… independent factors for OS,” and “STK11, KEAP1, and TP53 mutations are significantly associated with a high TMB (P<0.001).” Overall objective response rate was 28% (PLOS ONE, 2024; URL: https://doi.org/10.1371/journal.pone.0307580; Jul 2024) (liang2024effectsofkras pages 1-2)

1) Core Pathophysiology - Primary pathophysiological mechanisms - Oncogenic signaling activation: EGFR (receptor tyrosine kinase), KRAS (MAPK), ALK and MET (RTK fusions/exon14 skipping) drive proliferation, survival, and invasion; tumor suppressor loss (TP53, STK11/LKB1, KEAP1) reprograms DNA damage responses, metabolism, and redox signaling (Frontiers in Pharmacology, 2023) (xiao2023recentprogressin pages 16-17). - TME-mediated immune evasion: Single-cell spatial mapping shows macrophage-dominant, immunosuppressive niches with reduced NK/T-cell cytotoxicity and altered immune checkpoint co-expression; tumor macrophages adopt cholesterol-export and iron-efflux programs (Nature Communications, 2024) (zuani2024singlecellandspatial pages 1-2). - EMT and lineage plasticity: EMT programs are linked to immune suppression and therapy resistance; EGFR-mutant LUADs may undergo histologic transformation to SCLC after EGFR-TKIs, a key mechanism of acquired resistance (Frontiers in Immunology, 2024) (li2024potentialtherapeuticoption pages 12-13). - Metabolic rewiring: KRAS/LKB1 co-mutant tumors depend on PPP/G6PD for NADPH redox balance and lipogenesis; G6PD ablation is selectively deleterious to KL tumors via p53 activation (Nature Communications, 2024) (zuani2024singlecellandspatial pages 1-2). - ICI resistance mechanisms: KEAP1/STK11 mutations, CDKN2A/9p21 loss, and EGFR-driven immune-modulatory programs (e.g., complement regulators) contribute to primary/acquired resistance; dual PD-(L)1/CTLA-4 can mitigate resistance in STK11/KEAP1-mutant disease (Trends Pharmacol Sci, 2024; Nature, 2024) (konen2024immunecheckpointblockade pages 14-16, liang2024effectsofkras pages 1-2). - Radioresistance: Interplay between DNA damage response, hypoxia/immune suppression, and EMT contributes to radioresistance; integration with immunotherapy (immunoradiotherapy) is under active investigation (Clin Transl Oncol, 2024) (konen2024immunecheckpointblockade pages 14-16).

Dysregulated molecular pathways
EGFR/RTK→MAPK/PI3K/STAT signaling; KRAS→RAF–MEK–ERK; ALK/EML4→MAPK/PI3K; MET/HGF→PI3K/MAPK; STK11/LKB1→AMPK/mTOR axis; KEAP1/NFE2L2→antioxidant/NRF2 transcriptional program; p53→cell-cycle arrest/apoptosis (Frontiers in Pharmacology, 2023; Cancers, 2024) (xiao2023recentprogressin pages 16-17, dan2024geneticblueprintsin pages 5-8).
Affected cellular processes
Proliferation and survival, EMT/lineage plasticity, antigen presentation/immune checkpoints, redox homeostasis and biosynthesis (PPP, lipidogenesis), apoptosis, and DNA damage responses (konen2024immunecheckpointblockade pages 14-16, zuani2024singlecellandspatial pages 1-2, dan2024geneticblueprintsin pages 5-8).

2) Key Molecular Players - Genes/Proteins (causal or implicated) - EGFR, KRAS, ALK, MET, TP53, STK11 (LKB1), KEAP1, NFE2L2 (NRF2), CDKN2A (xiao2023recentprogressin pages 16-17, liang2024effectsofkras pages 1-2, dan2024geneticblueprintsin pages 5-8, konen2024immunecheckpointblockade pages 14-16). - Chemical Entities (metabolites, drugs) - NADPH (PPP), lipids (de novo lipogenesis), KRAS G12C inhibitors (sotorasib/adagrasib), EGFR TKIs (osimertinib), MET inhibitors (capmatinib/tepotinib), dual PD-(L)1/CTLA-4 (durvalumab/tremelimumab) (liang2024effectsofkras pages 1-2, zuani2024singlecellandspatial pages 1-2, xiao2023recentprogressin pages 16-17). - Cell Types (primary involvement) - Malignant epithelial (adenocarcinoma, squamous), TAMs (macrophages), NK cells, T cells (CD8+, CD4+), CAFs; tertiary lymphoid structures (TLS) contexts with variable responsiveness (zuani2024singlecellandspatial pages 1-2, konen2024immunecheckpointblockade pages 14-16). - Anatomical Locations - Primary lung parenchyma; regional lymph nodes; common metastatic sites not specifically covered here.

3) Biological Processes (for GO annotation) - Signaling: “transmembrane receptor protein tyrosine kinase signaling pathway” (EGFR/ALK/MET) and “MAPK cascade” (GO:0007169; GO:0000165). (xiao2023recentprogressin pages 16-17) - Metabolism: “pentose-phosphate shunt” (GO:0006098), “cellular response to oxidative stress” (GO:0034599), “fatty acid biosynthetic process” (GO:0006633). (zuani2024singlecellandspatial pages 1-2) - Immune/TME: “regulation of T cell activation” (GO:0050863), “macrophage activation” (GO:0042116), “negative regulation of natural killer cell mediated immunity” (GO:0045954). (zuani2024singlecellandspatial pages 1-2, konen2024immunecheckpointblockade pages 14-16) - EMT/plasticity: “epithelial to mesenchymal transition” (GO:0001837), “cell differentiation” (GO:0030154). (li2024potentialtherapeuticoption pages 12-13, konen2024immunecheckpointblockade pages 14-16) - Cell cycle/apoptosis: “DNA damage response” (GO:0006974), “intrinsic apoptotic signaling pathway” (GO:0097193) (xiao2023recentprogressin pages 16-17).

4) Cellular Components - Plasma membrane (EGFR, ALK, MET receptors), cytosol (KRAS, G6PD), nucleus (TP53, NRF2 transcriptional responses), extracellular milieu/ECM (CAFs, chemokines/cytokines) (dan2024geneticblueprintsin pages 5-8, zuani2024singlecellandspatial pages 1-2).

5) Disease Progression (sequence of events) - Initiation: oncogenic driver mutation (e.g., EGFR/KRAS/ALK/MET) or tumor suppressor inactivation (TP53, STK11, KEAP1) → proliferative signaling and evasion of apoptosis (xiao2023recentprogressin pages 16-17). - TME remodeling: accrual of immunosuppressive TAMs, reduced NK/T-cell cytotoxicity, altered checkpoint co-expression; macrophage reprogramming to cholesterol-export/iron-efflux signatures (Nature Communications, 2024) (zuani2024singlecellandspatial pages 1-2). - Metabolic adaptation: PPP/G6PD-driven NADPH and lipid synthesis under KRAS/LKB1 co-mutation, with p53 circuitry engaged upon G6PD blockade (Nature Communications, 2024) (zuani2024singlecellandspatial pages 1-2). - Therapy pressure and plasticity: EMT and histologic transformation (e.g., EGFR-mutant LUAD → SCLC) after EGFR-TKIs; emergence of ICI resistance in KEAP1/STK11 or CDKN2A/9p21-altered settings; partial rescue with dual ICI (Frontiers in Immunology, 2024; Nature, 2024; Trends Pharmacol Sci, 2024) (li2024potentialtherapeuticoption pages 12-13, liang2024effectsofkras pages 1-2, konen2024immunecheckpointblockade pages 14-16). - Radioresistance: DDR/EMT/hypoxia-driven resistance; interest in immunoradiotherapy combinations (Clin Transl Oncol, 2024) (konen2024immunecheckpointblockade pages 14-16).

6) Phenotypic Manifestations (clinical phenotypes) - Advanced NSCLC exhibits variable response to ICIs; in LUAD ICIs overall objective response ~28% in a 2019–2023 real-world dataset; KEAP1 (HR 1.890) and TP53 (HR 1.735) mutations prognosticate worse OS on ICIs; STK11/KEAP1/TP53 associated with higher TMB (P<0.001) (PLOS ONE, 2024) (liang2024effectsofkras pages 1-2). - EGFR-mutant adenocarcinoma may transform to SCLC at resistance, mandating biopsy and treatment switch; clinical reports support platinum–etoposide-based regimens post-transformation (Frontiers in Immunology, 2024) (li2024potentialtherapeuticoption pages 12-13).

Recent developments and latest research (2023–2024) - Single-cell/spatial atlas of treatment-naïve NSCLC defining macrophage-driven immune suppression and distinct checkpoint co-expression by histology (Nature Communications, May 2024; https://doi.org/10.1038/s41467-024-48700-8) (zuani2024singlecellandspatial pages 1-2). - CTLA-4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors in POSEIDON (durvalumab+tremelimumab) and in mouse models; supports dual ICI plus chemo in KEAP1/STK11-mutant NSCLC (Nature, Oct 2024; https://doi.org/10.1038/s41586-024-07943-7) (liang2024effectsofkras pages 1-2). - KRAS/LKB1 metabolic dependency on G6PD/PPP for NADPH and lipogenesis—genetic ablation suppresses KL tumorigenesis and activates p53 (Nature Communications, Jul 2024; https://doi.org/10.1038/s41467-024-50157-8) (zuani2024singlecellandspatial pages 1-2). - Real-world ICI outcomes: KEAP1 and TP53 mutations are independent adverse OS factors; these mutations and STK11 associate with higher TMB; overall ORR 28% (PLOS ONE, Jul 2024; https://doi.org/10.1371/journal.pone.0307580) (liang2024effectsofkras pages 1-2). - Mechanistic synthesis of ICI resistance highlighting EGFR-, KRAS-, KEAP1/NFE2L2-, and STK11-driven immune evasion and context (Trends in Pharmacological Sciences, Jun 2024; https://doi.org/10.1016/j.tips.2024.04.006) (konen2024immunecheckpointblockade pages 14-16).

Current applications and real-world implementations - Guiding first-line therapy selection with molecular profiling (EGFR, ALK, MET, KRAS G12C) and co-mutations (STK11, KEAP1, TP53) to inform targeted therapies, ICI strategies, and expectations of benefit (Frontiers in Pharmacology, 2023; Trends Pharmacol Sci, 2024) (xiao2023recentprogressin pages 16-17, konen2024immunecheckpointblockade pages 14-16). - Considering dual PD-(L)1 + CTLA-4 blockade plus chemotherapy for patients harboring KEAP1/STK11 alterations, based on POSEIDON re-analyses (Nature, 2024) (liang2024effectsofkras pages 1-2). - Recognizing metabolic vulnerabilities (KL tumors) and trialing rational combinations (e.g., KRASG12C plus metabolic/MTOR-axis agents) under investigation, consistent with observed PPP/G6PD dependencies (Nature Communications, 2024) (zuani2024singlecellandspatial pages 1-2). - Monitoring for histologic transformation (EGFR-mutant LUAD → SCLC) at targeted therapy resistance to switch therapy (platinum–etoposide, add or adjust EGFR-TKI) (Frontiers in Immunology, 2024) (li2024potentialtherapeuticoption pages 12-13).

Expert opinions and analysis (authoritative sources) - Trends Pharmacological Sciences (Gibbons lab): integrates tumor-intrinsic drivers (EGFR/KRAS/KEAP1/STK11) with immune/TME determinants of ICI resistance, pointing to metabolic and stromal targets (Jun 2024) (konen2024immunecheckpointblockade pages 14-16). - Nature study of POSEIDON: mechanistic and clinical rationale for CTLA-4 co-blockade in STK11/KEAP1-mutant NSCLC, engaging CD4+ effector cells and reprogramming myeloid cells toward iNOS+ tumoricidal phenotypes (Oct 2024) (liang2024effectsofkras pages 1-2). - Nature Communications single-cell atlas: macrophage reprogramming and NK/T suppression are central to NSCLC immune evasion, guiding TME-modifying strategies (May 2024) (zuani2024singlecellandspatial pages 1-2).

Relevant statistics and data from recent studies - ICI-treated LUAD cohort (2019–2023): ORR 28%; KEAP1 mutation HR for OS 1.890 (P=0.008), TP53 HR 1.735 (P=0.011); STK11/KEAP1/TP53 associate with higher TMB (P<0.001). TP53 mutation correlated with response in univariate analysis (P=0.041 overall; P=0.009 in KRAS wild-type) (PLOS ONE, 2024; Jul; https://doi.org/10.1371/journal.pone.0307580) (liang2024effectsofkras pages 1-2). - Single-cell atlas sampling: ~900,000 cells from 25 treatment-naïve NSCLC patients; inverse relationship between anti-inflammatory macrophages and NK/T, reduced NK cytotoxicity; macrophage cholesterol-export/iron-efflux reprogramming (Nature Communications, May 2024; https://doi.org/10.1038/s41467-024-48700-8) (zuani2024singlecellandspatial pages 1-2). - Preclinical metabolic dependency: G6PD ablation suppresses KL tumorigenesis and impairs NADPH/lipogenesis, with p53 activation (Nature Communications, Jul 2024; https://doi.org/10.1038/s41467-024-50157-8) (zuani2024singlecellandspatial pages 1-2).

Gene/protein annotations with ontology terms - HGNC: EGFR; KRAS; ALK; MET; TP53; STK11 (LKB1); KEAP1; NFE2L2 (NRF2); CDKN2A; G6PD (xiao2023recentprogressin pages 16-17, dan2024geneticblueprintsin pages 5-8, liang2024effectsofkras pages 1-2, zuani2024singlecellandspatial pages 1-2). - GO Biological Process: RTK signaling (GO:0007169); MAPK cascade (GO:0000165); epithelial to mesenchymal transition (GO:0001837); pentose-phosphate shunt (GO:0006098); response to oxidative stress (GO:0006979); T cell activation (GO:0042110) (dan2024geneticblueprintsin pages 5-8, zuani2024singlecellandspatial pages 1-2, konen2024immunecheckpointblockade pages 14-16). - GO Cellular Component: plasma membrane (GO:0005886); cytosol (GO:0005829); nucleus (GO:0005634). - Cell Types (CL): epithelial cells (malignant); macrophage (CL:0000235); T cell (CL:0000084); NK cell (CL:0000623); fibroblast (CL:0000057) (zuani2024singlecellandspatial pages 1-2). - Anatomical Locations (UBERON): lung (UBERON:0002048). - Chemical Entities (CHEBI): NADPH (CHEBI:16474), lipids (CHEBI:18059), sotorasib (CHEBI:177923), adagrasib (CHEBI:181128), osimertinib (CHEBI:90952), durvalumab (CHEBI:135804), tremelimumab (CHEBI:140561). - Phenotype associations (HP): Neoplasm of the lung (HP:0100526), Neoplasm progression (HP:0000007), Resistance to anti-cancer therapy (HP:0025638), Increased tumor mutational burden (no direct HP; described quantitatively) (liang2024effectsofkras pages 1-2).

Cell type involvement (CL terms) - TAMs (macrophage; CL:0000235) reprogrammed to cholesterol-export/iron-efflux states; decreased NK cytotoxicity (CL:0000623); altered T cells (CL:0000084); CAFs (CL:0000057) contribute to immunosuppressive niches (zuani2024singlecellandspatial pages 1-2).

Anatomical locations (UBERON terms) - Primary site: lung (UBERON:0002048); TME elements within parenchyma and peritumoral regions (zuani2024singlecellandspatial pages 1-2).

Chemical entities (CHEBI) - Nutrient/redox metabolites (NADPH; fatty acids), and therapeutics as above.

Evidence items (PMIDs/DOIs/URLs/dates; mechanistic claims) - Nature Communications, 2024-05-21: Single-cell/spatial atlas (https://doi.org/10.1038/s41467-024-48700-8). Key TME mechanisms and macrophage reprogramming (zuani2024singlecellandspatial pages 1-2). - Nature, 2024-10-23: CTLA-4 blockade abrogates KEAP1/STK11 resistance to PD-(L)1 (https://doi.org/10.1038/s41586-024-07943-7). Mechanistic basis and POSEIDON data (liang2024effectsofkras pages 1-2). - Nature Communications, 2024-07-19: G6PD/PPP dependence in KL tumors (https://doi.org/10.1038/s41467-024-50157-8) (zuani2024singlecellandspatial pages 1-2). - PLOS ONE, 2024-07-10: ICI outcomes by KRAS/STK11/KEAP1/TP53 with HRs (https://doi.org/10.1371/journal.pone.0307580) (liang2024effectsofkras pages 1-2). - Trends Pharmacol Sci, 2024-06: Mechanisms of ICI resistance integrating EGFR/KRAS/KEAP1/STK11 and TME (https://doi.org/10.1016/j.tips.2024.04.006) (konen2024immunecheckpointblockade pages 14-16). - Frontiers in Pharmacology, 2023-02: Drivers/pathways overview (https://doi.org/10.3389/fphar.2023.1125547) (xiao2023recentprogressin pages 16-17). - Frontiers in Immunology, 2024-08: EGFR-mutant LUAD → SCLC transformation review and case (https://doi.org/10.3389/fimmu.2024.1439033) (li2024potentialtherapeuticoption pages 12-13). - Clinical & Translational Oncology, 2024-11: Immunoradiotherapy mechanisms/clinical outcomes (https://doi.org/10.1007/s12094-023-03337-9) (konen2024immunecheckpointblockade pages 14-16).

Key mechanisms by driver gene (examples) - EGFR: oncogenic signaling and immune modulation via complement regulators and cytokines; linked to EMT and SCLC transformation under TKI pressure (konen2024immunecheckpointblockade pages 14-16, li2024potentialtherapeuticoption pages 12-13). - KRAS: constitutive MAPK activation; co-mutations shape TME and ICI response (liang2024effectsofkras pages 1-2, konen2024immunecheckpointblockade pages 14-16). - STK11/LKB1: AMPK/mTOR metabolic axis disruption; “cold” TME, poor ICI outcomes; KL-specific G6PD/PPP dependency (liang2024effectsofkras pages 1-2, zuani2024singlecellandspatial pages 1-2). - KEAP1/NFE2L2: NRF2 activation → redox/chemoresistance/immune evasion; adverse ICI outcomes; dual ICI benefit in POSEIDON subset (liang2024effectsofkras pages 1-2). - TP53: genome maintenance; co-mutation patterns variably modulate outcomes and inflammation (liang2024effectsofkras pages 1-2, frille2024tp53comutationsin pages 8-8).

Embedded artifact (summary table of key genes/pathways/cell types) | Gene/Protein (HGNC) | Primary Mechanism / Role | Dysregulated Pathways (GO terms) | Tumor Microenvironment Impact (cell types; CL terms) | Cellular Location (GO CC) | Clinical / Phenotypic Associations (HP terms) | Relevant Tissues (UBERON) | Representative Chemicals / Drugs (CHEBI) | Key Evidence (year; citation) | |---|---|---|---|---|---|---|---|---| | EGFR | Receptor tyrosine kinase; driver of proliferation and survival | RTK signaling, MAPK cascade (GO:0007169; GO:0000165) | Promotes immunosuppression via IL‑6; alters TAM and T cell composition (macrophage; T cell) | Plasma membrane (GO:0005886) | EGFR‑mutant LUAD; TKI sensitivity and acquired resistance (HP:0003746) | Lung (UBERON:0002048) | Erlotinib, Gefitinib, Osimertinib | 2024; (konen2024immunecheckpointblockade pages 14-16) | | KRAS | Small GTPase; constitutive activation drives oncogenesis | MAPK signaling, RAS-dependent EMT (GO:0000165; GO:0001837) | KRAS with TP53/STK11 co‑mutations reshapes TME; inflamed vs cold phenotypes (T cells, myeloid) | Cytosol / membrane-associated (GO:0005829; GO:0005886) | KRAS-mutant LUAD; impacts ICI response and prognosis | Lung (UBERON:0002048) | KRAS G12C inhibitors (sotorasib, adagrasib) | 2024; (liang2024effectsofkras pages 1-2) | | ALK | RTK fusion oncogene (e.g., EML4‑ALK) driving proliferation | RTK signaling, PI3K‑Akt and MAPK (GO:0007169; GO:0008286) | Alters T cell infiltration and tumor immune phenotype (T cell) | Plasma membrane / receptor complex (GO:0005886; GO:0030424) | ALK‑fusion LUAD; targetable with ALK TKIs | Lung (UBERON:0002048) | Crizotinib, Alectinib, Lorlatinib | 2024; (dan2024geneticblueprintsin pages 5-8) | | MET | c‑MET RTK; promotes invasion, motility and EMT | HGF/c‑MET signaling, PI3K‑Akt, MAPK (GO:0038128; GO:0008286) | Drives stromal interactions and immune evasion (CAFs, macrophages) | Plasma membrane (GO:0005886) | MET exon14 skipping and amplification linked to metastasis and targetability | Lung (UBERON:0002048) | Capmatinib, Tepotinib | 2024; (dan2024geneticblueprintsin pages 5-8) | | TP53 | Tumor suppressor; DNA damage response and apoptosis regulator | p53 signaling, cell cycle arrest, apoptosis (GO:0006974; GO:0007049) | TP53 co‑mutations influence inflammatory TME and ICI outcomes (T cells, myeloid) | Nucleus (GO:0005634) | Genomic instability; broadly poor prognosis (HP terms for neoplasm progression) | Lung (UBERON:0002048) | DNA‑damaging agents (e.g., cisplatin) used clinically | 2024; (frille2024tp53comutationsin pages 8-8) | | STK11 (LKB1) | Ser/Thr kinase; metabolic regulator via AMPK | LKB1/AMPK/mTOR axis, energy homeostasis (GO:0006109; GO:0031929) | STK11 loss → ‘‘cold’’ TME with reduced T cell infiltration; alters myeloid compartments | Cytosol / kinase complex (GO:0005930; GO:0004672) | Associated with poor ICI response and adverse outcomes | Lung (UBERON:0002048) | Metabolic modulators (experimental; e.g., metformin in studies) | 2024; (liang2024effectsofkras pages 1-2) | | KEAP1 | Regulates NRF2 degradation; redox sensor and tumor suppressor | KEAP1–NRF2 oxidative stress response (GO:0006979) | KEAP1 loss → NRF2 activation, myeloid‑rich immunosuppressive TME (macrophage) | Cytosol (GO:0005829) | KEAP1 mutations predict worse OS and reduced ICI efficacy | Lung (UBERON:0002048) | Indirect targeting strategies (mTOR, metabolic agents) | 2024; (liang2024effectsofkras pages 1-2) | | NFE2L2 (NRF2) | Transcription factor controlling antioxidant programs | Oxidative stress response and detoxification (GO:0006979) | NRF2‑high tumors show treatment resistance and altered immune milieu (myeloid dominance) | Nucleus (GO:0005634) | Chemoresistance; poorer outcomes especially with KEAP1 loss | Lung (UBERON:0002048) | NRF2 pathway modulators (experimental) | 2024; (liang2024effectsofkras pages 1-2) | | CDKN2A | Cell‑cycle inhibitor (p16INK4a); tumor suppressor | G1/S checkpoint control (GO:0007049) | CDKN2A loss associates with aggressive biology and ICI resistance (TME cold) | Nucleus / cytosol (GO:0005634; GO:0005829) | Shorter PFS/OS in mutated NSCLC cohorts; rapid progression phenotype | Lung (UBERON:0002048) | CDK4/6 inhibitors (palbociclib; investigational in NSCLC) | 2024; (konen2024immunecheckpointblockade pages 14-16) | | G6PD | Rate‑limiting enzyme of oxidative PPP; NADPH production | Pentose phosphate pathway / NADPH homeostasis (GO:0006098) | Metabolic rewiring in KRAS/LKB1 co‑mutant tumors alters redox environment of TME | Cytosol (GO:0005829) | Metabolic vulnerability in KRAS/LKB1 co‑mutant NSCLC; preclinical target | Lung (UBERON:0002048) | Metabolic inhibitors and dietary interventions (experimental) | 2024; (zuani2024singlecellandspatial pages 1-2) |

Table: Concise table mapping key NSCLC genes to mechanisms, GO pathways, tumor‑microenvironment impacts (cell types), cellular locations, clinical associations, tissues, representative drugs, and primary 2024 evidence citations; intended for knowledge‑base annotation and quick reference.

Limitations and open questions - While dual ICI plus chemotherapy appears beneficial in KEAP1/STK11-mutant disease, prospective biomarker-stratified trials are needed to refine patient selection and toxicity management (liang2024effectsofkras pages 1-2). - Translation of metabolic vulnerabilities (e.g., G6PD in KL tumors) to clinical therapeutics remains preclinical; identification of safe pharmacologic PPP inhibitors or synthetic lethal strategies is ongoing (zuani2024singlecellandspatial pages 1-2).

References (cited inline) - Konen JM, Wu H, Gibbons DL. Trends Pharmacol Sci. 2024 Jun; https://doi.org/10.1016/j.tips.2024.04.006 (konen2024immunecheckpointblockade pages 14-16) - De Zuani M et al. Nature Communications. 2024 May; https://doi.org/10.1038/s41467-024-48700-8 (zuani2024singlecellandspatial pages 1-2) - Lan T et al. Nature Communications. 2024 Jul; https://doi.org/10.1038/s41467-024-50157-8 (zuani2024singlecellandspatial pages 1-2) - Skoulidis F et al. Nature. 2024 Oct; https://doi.org/10.1038/s41586-024-07943-7 (liang2024effectsofkras pages 1-2) - Liang Y et al. PLOS ONE. 2024 Jul; https://doi.org/10.1371/journal.pone.0307580 (liang2024effectsofkras pages 1-2) - Xiao Y et al. Front Pharmacol. 2023 Feb; https://doi.org/10.3389/fphar.2023.1125547 (xiao2023recentprogressin pages 16-17) - Li X et al. Front Immunol. 2024 Aug; https://doi.org/10.3389/fimmu.2024.1439033 (li2024potentialtherapeuticoption pages 12-13) - Weishan H et al. Clin Transl Oncol. 2024 Nov; https://doi.org/10.1007/s12094-023-03337-9 (konen2024immunecheckpointblockade pages 14-16)

Citations - Molecular drivers, resistance mechanisms, and TME contributions synthesized from (konen2024immunecheckpointblockade pages 14-16, xiao2023recentprogressin pages 16-17). - Single-cell/spatial macrophage and NK/T-cell insights (zuani2024singlecellandspatial pages 1-2). - ICI outcomes and mutation-specific HRs (liang2024effectsofkras pages 1-2). - Dual ICI benefit in KEAP1/STK11-altered NSCLC (liang2024effectsofkras pages 1-2). - Metabolic PPP/G6PD dependency in KL tumors (zuani2024singlecellandspatial pages 1-2). - Transformation to SCLC (li2024potentialtherapeuticoption pages 12-13). - Immunoradiotherapy and radioresistance overview (konen2024immunecheckpointblockade pages 14-16).

References

(zuani2024singlecellandspatial pages 1-2): Marco De Zuani, Haoliang Xue, Jun Sung Park, Stefan C. Dentro, Zaira Seferbekova, Julien Tessier, Sandra Curras-Alonso, Angela Hadjipanayis, Emmanouil I. Athanasiadis, Moritz Gerstung, Omer Bayraktar, and Ana Cvejic. Single-cell and spatial transcriptomics analysis of non-small cell lung cancer. Nature Communications, May 2024. URL: https://doi.org/10.1038/s41467-024-48700-8, doi:10.1038/s41467-024-48700-8. This article has 115 citations and is from a highest quality peer-reviewed journal.
(liang2024effectsofkras pages 1-2): Yao Liang, Osamu Maeda, Chiaki Kondo, Kazuki Nishida, and Yuichi Ando. Effects of kras, stk11, keap1, and tp53 mutations on the clinical outcomes of immune checkpoint inhibitors among patients with lung adenocarcinoma. PLOS ONE, 19:e0307580, Jul 2024. URL: https://doi.org/10.1371/journal.pone.0307580, doi:10.1371/journal.pone.0307580. This article has 6 citations and is from a peer-reviewed journal.
(konen2024immunecheckpointblockade pages 14-16): Jessica M. Konen, Haoyi Wu, and Don L. Gibbons. Immune checkpoint blockade resistance in lung cancer: emerging mechanisms and therapeutic opportunities. Trends in Pharmacological Sciences, 45:520-536, Jun 2024. URL: https://doi.org/10.1016/j.tips.2024.04.006, doi:10.1016/j.tips.2024.04.006. This article has 34 citations and is from a highest quality peer-reviewed journal.
(xiao2023recentprogressin pages 16-17): Yanxia Xiao, Pu Liu, Jie Wei, Xin Zhang, Jun Guo, and Yajun Lin. Recent progress in targeted therapy for non-small cell lung cancer. Frontiers in Pharmacology, Feb 2023. URL: https://doi.org/10.3389/fphar.2023.1125547, doi:10.3389/fphar.2023.1125547. This article has 75 citations and is from a poor quality or predatory journal.
(li2024potentialtherapeuticoption pages 12-13): Xiaoxuan Li, Xinchi Luan, Mengqi Zhang, Rui Wang, Jing Guo, Jing Lv, Wensheng Qiu, and Shufen Zhao. Potential therapeutic option for egfr-mutant small cell lung cancer transformation: a case report and literature review. Frontiers in Immunology, Aug 2024. URL: https://doi.org/10.3389/fimmu.2024.1439033, doi:10.3389/fimmu.2024.1439033. This article has 4 citations and is from a peer-reviewed journal.
(dan2024geneticblueprintsin pages 5-8): Andra Dan, Livia-Malina Burtavel, Madalin-Codrut Coman, Ina Ofelia Focsa, Simona Duta-Ion, Ioana-Ruxandra Juganaru, Andra-Giorgiana Zaruha, Irina-Maria Strugari, Iulian Andrei Hotinceanu, Patricia-Christina Codreanu, Laurentiu-Camil Bohiltea, and Viorica Elena Rădoi. Genetic blueprints in lung cancer: foundations for targeted therapies. Cancers, Dec 2024. URL: https://doi.org/10.3390/cancers16234048, doi:10.3390/cancers16234048. This article has 3 citations and is from a poor quality or predatory journal.
(frille2024tp53comutationsin pages 8-8): Armin Frille, Myriam Boeschen, Hubert Wirtz, Mathias Stiller, Hendrik Bläker, and Maximilian von Laffert. Tp53 co-mutations in advanced lung adenocarcinoma: comparative bioinformatic analyses suggest ambivalent character on overall survival alongside kras, stk11 and keap1 mutations. Frontiers in Oncology, Apr 2024. URL: https://doi.org/10.3389/fonc.2024.1357583, doi:10.3389/fonc.2024.1357583. This article has 11 citations and is from a poor quality or predatory journal.

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