ALK-Rearranged Non-Small Cell Lung Cancer

MONDO:0005061 Pathograph 4 non-small cell lung carcinoma

ALK-rearranged non-small cell lung cancer (NSCLC) is a molecularly-defined lung cancer subtype driven by chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene. ALK fusions occur in approximately 3-7% of NSCLC, most commonly EML4-ALK resulting from an inversion on chromosome 2. ALK-positive NSCLC occurs predominantly in younger patients with minimal or no smoking history. Multiple generations of highly effective ALK tyrosine kinase inhibitors have transformed this disease from rapidly fatal to chronic manageable condition, although CNS relapse and acquired resistance remain major sequencing challenges.

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Mappings

Definitions

Inheritance

Differentials

Datasets

Trials

Models

References

Deep Research

🏷

Classifications

Harrison's Chapter

ICD-O Morphology

◆

Subtypes

EML4-ALK NSCLC

EML4-ALK translocation is a recurrent ALK-positive NSCLC subtype. Different ALK variants, resistance mutations, and co-mutations can influence treatment selection and sequencing; EML4-ALK variant 3 is associated with shorter PFS on ALK TKI therapy than variant 1 in pooled clinical data.

Show evidence (2 references)

DOI:10.3390/ijms26010308 SUPPORT Human Clinical

"the molecular profile of the disease, including mutation resistances and ALK variants and co-mutations"

Supports the clinical relevance of ALK variant and resistance biology in EML4-ALK-positive NSCLC.

PMID:41959926 SUPPORT Human Clinical

"V3 was associated with shorter progression-free survival (PFS)"

Meta-analysis supports variant 3 as an adverse PFS marker among patients receiving ALK TKI therapy.

Non-EML4 ALK Fusion NSCLC

Rare ALK fusions with partners other than EML4, including KIF5B-ALK, TFG-ALK, and KLC1-ALK. Generally respond similarly to ALK TKIs.

Show evidence (1 reference)

DOI:10.3390/biomedicines12020297 SUPPORT Human Clinical

"Approximately 3–5% of NSCLC patients exhibit complex ALK rearrangements"

Comprehensive review notes the diversity of ALK rearrangements including non-EML4 partner genes.

⚙

Pathophysiology

ALK Gene Rearrangement

ALK rearrangements result from chromosomal inversions or translocations that fuse the ALK kinase domain to an N-terminal partner gene (usually EML4). The partner provides a dimerization domain, causing constitutive ALK kinase activation independent of ligand.

type II pneumocyte link

protein phosphorylation link ↑ INCREASED

Downstream

Constitutive ALK Signaling Fusion protein is constitutively active

Show evidence (2 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."

This abstract states that ALK rearrangements drive a subset of NSCLC, supporting the ALK gene rearrangement mechanism.

CIVIC_ASSERTION:3 SUPPORT Other

"ALK-FUSIONS are found in 3-5% of non-small cell lung cancer and act as a targetable driver mutation."

CIViC's accepted assertion supports ALK fusions as targetable driver alterations in NSCLC.

Constitutive ALK Signaling

The EML4-ALK fusion protein is constitutively dimerized and auto-phosphorylated, activating downstream signaling including RAS-MAPK, PI3K-AKT, and JAK-STAT3 pathways. These pathways promote cell proliferation, survival, and migration.

MAPK cascade link ↑ INCREASED phosphatidylinositol 3-kinase signaling link ↑ INCREASED JAK-STAT cascade link ↑ INCREASED

Downstream

Oncogene Addiction Tumor survival dependent on ALK activity

Show evidence (1 reference)

DOI:10.1177/03008916231202149 SUPPORT Human Clinical

"ALK is constitutively activated by gene fusion events between the ALK and other gene fusion partners in about 2-3% of LUADs"

Direct support that ALK fusion events drive constitutive kinase signaling.

Oncogene Addiction

ALK-rearranged tumors exhibit oncogene addiction, becoming dependent on continued ALK signaling for survival. ALK inhibition leads to dramatic tumor responses, often within days to weeks of starting therapy.

cell population proliferation link ↑ INCREASED

Downstream

ALK TKI Resistance Selective pressure from ALK-targeted therapy drives emergence of resistance mutations and bypass pathways

Show evidence (1 reference)

PMID:27637426 SUPPORT Human Clinical

"the oncologic community searched for other molecular subsets featuring oncogene addiction. An early result of this search was the discovery of NSCLC driven by activating rearrangements of the anaplastic lymphoma kinase (ALK) gene."

Frames ALK-rearranged NSCLC as the classic oncogene-addicted molecular subset.

ALK TKI Resistance

Resistance to ALK TKIs develops through ALK-dependent mechanisms (secondary mutations like G1202R, compound mutations) or ALK-independent bypass pathways (MET, EGFR, KRAS, SRC, AXL/YAP). Microenvironmental HGF-MET and integrin signaling, EMT, and bypass kinase activation can sustain resistant growth; later-generation TKIs such as lorlatinib overcome many single ALK mutations but not all compound or bypass states.

response to drug link ⚠ ABNORMAL

Show evidence (6 references)

DOI:10.1177/03008916231202149 SUPPORT Human Clinical

"resistance mechanisms greatly limit the durability of the therapeutic effects elicited by these TKIs"

Confirms acquired resistance as a defining clinical challenge of ALK-targeted therapy.

PMID:28676215 SUPPORT Human Clinical

"The co-crystal structure of ceritinib/ALK demonstrates a strong interaction between ceritinib and the P-loop which is facilitated by T1151 on the β3 sheet, a feature not present in the alectinib/ALK or lorlatinib/ALK co-crystal structure."

Co-crystal structures explain differential sensitivity of ALK resistance mutations to different inhibitors, supporting the ALK-dependent resistance mechanism.

PMID:35085771 SUPPORT In Vitro

"induced an epithelial-mesenchymal transition (EMT)"

Supports EMT as a cellular phenotype linked to ALK G1202R-mediated TKI resistance.

+ 3 more references

✶

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.

⬡

Pathograph

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

●

Phenotypes

Lung Adenocarcinoma VERY_FREQUENT Neoplastic HP:0030078

Show evidence (1 reference)

DOI:10.1177/03008916231202149 SUPPORT Human Clinical

"Anaplastic Lymphoma Kinase (ALK) is a potent oncogenic driver of lung adenocarcinoma (LUAD)."

Confirms lung adenocarcinoma as the histologic context for ALK-rearranged tumors.

Young Age at Diagnosis VERY_FREQUENT Clinical HP:0100526

Show evidence (1 reference)

PMID:37007097 SUPPORT Human Clinical

"Anaplastic lymphoma kinase (ALK) fusion mutation is more common in younger and never-smoking lung cancer patients."

Directly supports younger age enrichment in ALK fusion-positive lung cancer.

Never/Light Smoker VERY_FREQUENT Clinical HP:0100526

Show evidence (1 reference)

PMID:37007097 SUPPORT Human Clinical

"179 (27.5) smokers, 461 (70.9%) never-smokers, 10 (1.5%) with unknown smoking status"

In a real-world cohort of ALK-positive advanced lung adenocarcinoma, most patients with known smoking status were never-smokers.

Brain Metastases FREQUENT Clinical HP:0004375

Show evidence (3 references)

PMID:34147645 SUPPORT Human Clinical

"Brain metastases are quite frequent in patients with ALK-translocated non-small cell lung cancer (NSCLC)"

Directly supports brain metastases as a frequent clinical manifestation of ALK-translocated NSCLC.

PMID:40024442 SUPPORT Human Clinical

"the intracranial objective response rate was 69%"

Five-year CROWN subgroup data support strong intracranial activity for first-line lorlatinib in patients with baseline brain metastases.

PMID:38598794 SUPPORT Human Clinical

"clinically meaningful benefit with respect to CNS disease-free"

ALINA supports CNS disease-free survival benefit with adjuvant alectinib versus chemotherapy.

🧬

Genetic Associations

ALK (Somatic Rearrangement)

Somatic

Show evidence (2 references)

PMID:27637426 SUPPORT Human Clinical

"the discovery of NSCLC driven by activating rearrangements of the anaplastic lymphoma kinase (ALK) gene"

Establishes ALK gene rearrangements as the defining genetic lesion of this NSCLC subset.

CIVIC_ASSERTION:3 SUPPORT Other

"ALK-FUSIONS are found in 3-5% of non-small cell lung cancer and act as a targetable driver mutation."

CIViC's accepted assertion supports ALK fusions as defining, targetable genetic drivers in NSCLC.

EML4 (Fusion Partner)

Somatic

Show evidence (1 reference)

DOI:10.1177/03008916231202149 SUPPORT Human Clinical

"ALK is constitutively activated by gene fusion events between the ALK and other gene fusion partners in about 2-3% of LUADs"

Supports EML4 (and other partners) as the fusion partner that drives constitutive ALK activation.

💊

Treatments

Alectinib

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

Agent: alectinib ↗

Second-generation ALK TKI with excellent CNS penetration. First-line standard of care based on ALEX trial showing superior PFS and OS vs crizotinib, and an adjuvant option for resected ALK-positive NSCLC based on ALINA. Active against many crizotinib-resistant mutations.

🔬 3D Structures:

3AOX X-ray 1.7 Å ⚗️ alectinib

Alectinib bound to the ALK kinase domain, revealing the unique binding mode that confers activity against crizotinib-resistant gatekeeper mutations

Show evidence (3 references)

DOI:10.3390/biomedicines12020297 SUPPORT Human Clinical

"second-generation TKIs such as alectinib, ceritinib, and brigatinib have emerged to address resistance issues initially associated with the pioneer ALK-TKI, crizotinib"

Establishes alectinib as a second-generation ALK TKI used to address crizotinib resistance.

PMID:38598794 SUPPORT Human Clinical

"adjuvant alectinib significantly improved disease-free survival"

ALINA supports alectinib as adjuvant therapy after resection of stage IB-IIIA ALK-positive NSCLC.

CIVIC_ASSERTION:34 SUPPORT Other

"ALK fusion positive NSCLC is sensitive to alectinib"

CIViC's accepted assertion directly supports alectinib sensitivity in ALK fusion-positive NSCLC.

Lorlatinib

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

Agent: lorlatinib ↗

Third-generation ALK TKI designed to overcome resistance mutations including G1202R. Excellent CNS activity. Can be used first-line based on CROWN, where five-year follow-up showed durable PFS advantage over crizotinib, or after progression on prior ALK TKIs.

🔬 3D Structures:

4CLI X-ray 1.65 Å ⚗️ lorlatinib

Lorlatinib bound to the ALK kinase domain, showing the macrocyclic scaffold that maintains binding despite the G1202R solvent-front resistance mutation

Show evidence (2 references)

PMID:28676215 SUPPORT Human Clinical

"a feature not present in the alectinib/ALK or lorlatinib/ALK co-crystal structure"

Co-crystal structures of lorlatinib/ALK demonstrate the binding mode that overcomes resistance mutations like T1151K and G1202R.

PMID:40024442 SUPPORT Human Clinical

"the five-year PFS was 63%"

Five-year CROWN subgroup data support durable first-line lorlatinib benefit over crizotinib.

Ceritinib

Action: pharmacotherapy MAXO:0000058

Agent: ceritinib ↗

Second-generation ALK TKI used in ALK-positive NSCLC, including settings where resistance to crizotinib is a concern. It is less favored than newer CNS-active ALK inhibitors in many current sequencing strategies but remains part of the ALK inhibitor class history.

Show evidence (1 reference)

DOI:10.3390/biomedicines12020297 SUPPORT Human Clinical

"second-generation TKIs such as alectinib, ceritinib, and brigatinib have emerged to address resistance issues initially associated with the pioneer ALK-TKI, crizotinib"

Directly identifies ceritinib as a second-generation ALK TKI used to address resistance issues after crizotinib.

Brigatinib

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

Agent: brigatinib ↗

Second-generation ALK TKI with broad activity against resistance mutations and good CNS penetration. Alternative to alectinib in first-line or subsequent settings.

Show evidence (1 reference)

DOI:10.3390/biomedicines12020297 SUPPORT Human Clinical

"second-generation TKIs such as alectinib, ceritinib, and brigatinib have emerged to address resistance issues initially associated with the pioneer ALK-TKI, crizotinib"

Establishes brigatinib among the second-generation ALK TKIs used to address crizotinib resistance.

Crizotinib

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

Agent: crizotinib ↗

First-generation ALK TKI that established proof-of-concept for ALK inhibition in lung cancer. Now largely replaced by more potent second/third generation agents due to lower CNS efficacy and resistance.

🔬 3D Structures:

2XP2 X-ray 1.86 Å ⚗️ crizotinib

Crizotinib bound to wild-type ALK kinase domain (RCSB title "Structure of the Human Anaplastic Lymphoma Kinase in Complex with Crizotinib"), showing the aminopyridine scaffold inserted into the ATP-binding cleft. Note 2WGJ is the c-Met/crizotinib co-crystal from the same paper.

Show evidence (2 references)

PMID:23805942 SUPPORT In Vitro

"The article highlights its beginning with the X-ray crystallographic structure of a lead compound (PHA-0665752) bound to the active site of the kinase domain of c-Met."

Preclinical structural biology directly enabled the discovery and development of crizotinib as the first ALK TKI for NSCLC.

CIVIC_ASSERTION:3 SUPPORT Other

"Lung adenocarcinoma positive for ALK-FUSIONS have been found to be sensitive to crizotinib treatment"

CIViC's accepted assertion directly supports crizotinib sensitivity in ALK fusion-positive NSCLC.

Chemotherapy

Action: chemotherapy MAXO:0000647

Pemetrexed-based chemotherapy, including platinum/pemetrexed regimens, is a cytotoxic treatment option in advanced ALK-positive NSCLC when targeted therapy options are exhausted or unavailable.

Show evidence (1 reference)

PMID:22887466 SUPPORT Human Clinical

"Among 70 ALK-positive patients treated with a platinum/pemetrexed regimen, the median PFS (mPFS) was 7.3 months"

Directly supports platinum/pemetrexed chemotherapy as a studied regimen in advanced ALK-positive NSCLC.

🔬

Biochemical Markers

ALK Testing

Show evidence (1 reference)

DOI:10.3390/biomedicines12020297 SUPPORT Human Clinical

"the review explores innovative directions such as ALK molecular diagnostics"

Comprehensive review highlights the central role of ALK molecular diagnostics in identifying eligible NSCLC patients.

🧮

Computational Models

ALK Kinase Domain Crystal Structure-Guided Drug Design STRUCTURAL_PREDICTION

X-ray crystallographic structures of lead compounds bound to the kinase domain of c-Met/ALK were instrumental in the structure-based development of crizotinib, the first FDA-approved ALK inhibitor for EML4-ALK-positive NSCLC. Crystal structures guided optimization of lipophilic efficiency and target binding, and continue to inform development of next-generation ALK inhibitors (ceritinib, alectinib, lorlatinib) that overcome resistance mutations.

PMID:23805942 ↗

Findings

X-ray crystallographic structure of a lead compound bound to c-Met kinase domain guided development of crizotinib

Co-crystal structures of ALK with different inhibitors explain resistance mutation profiles

Show evidence (2 references)

PMID:23805942 SUPPORT In Vitro

"The article highlights its beginning with the X-ray crystallographic structure of a lead compound (PHA-0665752) bound to the active site of the kinase domain of c-Met."

Demonstrates that structural biology directly guided the drug discovery process for the first ALK inhibitor crizotinib.

PMID:28676215 SUPPORT In Vitro

Co-crystal structures explain differential sensitivity of ALK resistance mutations to different inhibitors.

{ }

Source YAML

click to show

name: ALK-Rearranged Non-Small Cell Lung Cancer
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-05-11T02:45:15Z'
description: >-
ALK-rearranged non-small cell lung cancer (NSCLC) is a molecularly-defined lung
cancer subtype driven by chromosomal rearrangements involving the anaplastic
lymphoma kinase (ALK) gene. ALK fusions occur in approximately 3-7% of NSCLC,
most commonly EML4-ALK resulting from an inversion on chromosome 2. ALK-positive
NSCLC occurs predominantly in younger patients with minimal or no smoking history.
Multiple generations of highly effective ALK tyrosine kinase inhibitors have
transformed this disease from rapidly fatal to chronic manageable condition,
although CNS relapse and acquired resistance remain major sequencing challenges.
categories:
- Molecularly-Defined Cancer
- Lung Cancer Subtype
- Fusion Gene-Driven Cancer
- Solid Tumor
parents:
- non-small cell lung carcinoma
external_assertions:
- name: CIViC ALK fusion crizotinib sensitivity assertion
source: CIViC
assertion_type: accepted_assertion
external_id: CIVIC_ASSERTION:3
url: https://civicdb.org/links/assertions/3
description: >-
CIViC accepted assertion that ALK fusion-positive non-small cell lung
carcinoma predicts sensitivity/response to crizotinib.
notes: >-
01-May-2026 CIViC accepted assertion: molecular_profile="v::ALK Fusion";
disease="Lung Non-small Cell Carcinoma"; assertion_type=Predictive;
significance=Sensitivity/Response; therapy=Crizotinib; AMP category=Tier I - Level A.
evidence:
- reference: CIVIC_ASSERTION:3
reference_title: "v::ALK Fusion / Lung Non-small Cell Carcinoma (Predictive Sensitivity/Response)"
supports: SUPPORT
evidence_source: OTHER
snippet: Lung adenocarcinoma positive for ALK-FUSIONS have been found to be sensitive to crizotinib treatment
explanation: CIViC records an accepted predictive sensitivity assertion for ALK fusion and crizotinib in NSCLC.
- name: CIViC ALK fusion alectinib sensitivity assertion
source: CIViC
assertion_type: accepted_assertion
external_id: CIVIC_ASSERTION:34
url: https://civicdb.org/links/assertions/34
description: >-
CIViC accepted assertion that ALK fusion-positive non-small cell lung
carcinoma predicts sensitivity/response to alectinib.
notes: >-
01-May-2026 CIViC accepted assertion: molecular_profile="v::ALK Fusion";
disease="Lung Non-small Cell Carcinoma"; assertion_type=Predictive;
significance=Sensitivity/Response; therapy=Alectinib; AMP category=Tier I - Level A.
evidence:
- reference: CIVIC_ASSERTION:34
reference_title: "v::ALK Fusion / Lung Non-small Cell Carcinoma (Predictive Sensitivity/Response)"
supports: SUPPORT
evidence_source: OTHER
snippet: ALK fusion positive NSCLC is sensitive to alectinib
explanation: CIViC records an accepted predictive sensitivity assertion for ALK fusion and alectinib in NSCLC.
- name: CIViC EML4::ALK plus ALK G1202R crizotinib resistance evidence item
source: CIViC
assertion_type: accepted_evidence_item
external_id: CIVIC_EID:441
url: https://civicdb.org/links/evidence_items/441
description: >-
CIViC accepted evidence item linking EML4::ALK fusion with ALK G1202R in
non-small cell lung cancer to crizotinib resistance.
notes: >-
01-May-2026 CIViC accepted evidence item: molecular_profile="EML4::ALK
Fusion AND ALK G1202R"; evidence_type=Predictive; evidence_level=D;
significance=Resistance; therapy=Crizotinib; citation_id=PMID:22277784.
evidence:
- reference: CIVIC_EID:441
reference_title: "EML4::ALK Fusion AND ALK G1202R / Lung Non-small Cell Carcinoma (Predictive Resistance)"
supports: SUPPORT
evidence_source: OTHER
snippet: The G1202R mutation in the EML4-ALK fusion was found to confer resistance to crizotinib in Ba/F3 cells.
explanation: CIViC records an accepted predictive resistance evidence item for ALK G1202R and crizotinib in NSCLC.
has_subtypes:
- name: EML4-ALK NSCLC
description: >-
EML4-ALK translocation is a recurrent ALK-positive NSCLC subtype. Different
ALK variants, resistance mutations, and co-mutations can influence treatment
selection and sequencing; EML4-ALK variant 3 is associated with shorter PFS
on ALK TKI therapy than variant 1 in pooled clinical data.
evidence:
- reference: DOI:10.3390/ijms26010308
reference_title: "EML4-ALK: Update on ALK Inhibitors"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: the molecular profile of the disease, including mutation resistances and ALK variants and co-mutations
explanation: Supports the clinical relevance of ALK variant and resistance biology in EML4-ALK-positive NSCLC.
- reference: PMID:41959926
reference_title: A meta-analysis of the impact of different ALK variants on targeted therapy efficacy in advanced non-small cell lung cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: V3 was associated with shorter progression-free survival (PFS)
explanation: Meta-analysis supports variant 3 as an adverse PFS marker among patients receiving ALK TKI therapy.
- name: Non-EML4 ALK Fusion NSCLC
description: >-
Rare ALK fusions with partners other than EML4, including KIF5B-ALK,
TFG-ALK, and KLC1-ALK. Generally respond similarly to ALK TKIs.
evidence:
- reference: DOI:10.3390/biomedicines12020297
reference_title: "Unraveling the Potential of ALK-Targeted Therapies in Non-Small Cell Lung Cancer: Comprehensive Insights and Future Directions"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Approximately 3–5% of NSCLC patients exhibit complex ALK rearrangements
explanation: Comprehensive review notes the diversity of ALK rearrangements including non-EML4 partner genes.
pathophysiology:
- name: ALK Gene Rearrangement
description: >-
ALK rearrangements result from chromosomal inversions or translocations
that fuse the ALK kinase domain to an N-terminal partner gene (usually
EML4). The partner provides a dimerization domain, causing constitutive
ALK kinase activation independent of ligand.
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.
explanation: This abstract states that ALK rearrangements drive a subset of NSCLC, supporting the ALK gene rearrangement mechanism.
- reference: CIVIC_ASSERTION:3
reference_title: "v::ALK Fusion / Lung Non-small Cell Carcinoma (Predictive Sensitivity/Response)"
supports: SUPPORT
evidence_source: OTHER
snippet: ALK-FUSIONS are found in 3-5% of non-small cell lung cancer and act as a targetable driver mutation.
explanation: CIViC's accepted assertion supports ALK fusions as targetable driver alterations in NSCLC.
cell_types:
- preferred_term: type II pneumocyte
term:
id: CL:0002063
label: pulmonary alveolar type 2 cell
biological_processes:
- preferred_term: protein phosphorylation
modifier: INCREASED
term:
id: GO:0006468
label: protein phosphorylation
downstream:
- target: Constitutive ALK Signaling
description: Fusion protein is constitutively active
- name: Constitutive ALK Signaling
description: >-
The EML4-ALK fusion protein is constitutively dimerized and auto-phosphorylated,
activating downstream signaling including RAS-MAPK, PI3K-AKT, and JAK-STAT3
pathways. These pathways promote cell proliferation, survival, and migration.
evidence:
- reference: DOI:10.1177/03008916231202149
reference_title: "ALK-rearranged lung adenocarcinoma: From molecular genetics to therapeutic targeting"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: ALK is constitutively activated by gene fusion events between the ALK and other gene fusion partners in about 2-3% of LUADs
explanation: Direct support that ALK fusion events drive constitutive kinase signaling.
biological_processes:
- preferred_term: MAPK cascade
modifier: INCREASED
term:
id: GO:0000165
label: MAPK cascade
- preferred_term: phosphatidylinositol 3-kinase signaling
modifier: INCREASED
term:
id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
- preferred_term: JAK-STAT cascade
modifier: INCREASED
term:
id: GO:0007259
label: cell surface receptor signaling pathway via JAK-STAT
downstream:
- target: Oncogene Addiction
description: Tumor survival dependent on ALK activity
- name: Oncogene Addiction
description: >-
ALK-rearranged tumors exhibit oncogene addiction, becoming dependent on
continued ALK signaling for survival. ALK inhibition leads to dramatic
tumor responses, often within days to weeks of starting therapy.
evidence:
- reference: PMID:27637426
reference_title: "ALK alterations and inhibition in lung cancer."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: the oncologic community searched for other molecular subsets featuring oncogene addiction. An early result of this search was the discovery of NSCLC driven by activating rearrangements of the anaplastic lymphoma kinase (ALK) gene.
explanation: Frames ALK-rearranged NSCLC as the classic oncogene-addicted molecular subset.
downstream:
- target: ALK TKI Resistance
description: Selective pressure from ALK-targeted therapy drives emergence of resistance mutations and bypass pathways
biological_processes:
- preferred_term: cell population proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
- name: ALK TKI Resistance
description: >-
Resistance to ALK TKIs develops through ALK-dependent mechanisms (secondary
mutations like G1202R, compound mutations) or ALK-independent bypass
pathways (MET, EGFR, KRAS, SRC, AXL/YAP). Microenvironmental HGF-MET and
integrin signaling, EMT, and bypass kinase activation can sustain resistant
growth; later-generation TKIs such as lorlatinib overcome many single ALK
mutations but not all compound or bypass states.
evidence:
- reference: DOI:10.1177/03008916231202149
reference_title: "ALK-rearranged lung adenocarcinoma: From molecular genetics to therapeutic targeting"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: resistance mechanisms greatly limit the durability of the therapeutic effects elicited by these TKIs
explanation: Confirms acquired resistance as a defining clinical challenge of ALK-targeted therapy.
- reference: PMID:28676215
reference_title: "Identification of a novel T1151K ALK mutation in a patient with ALK-rearranged NSCLC with prior exposure to crizotinib and ceritinib."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The co-crystal structure of ceritinib/ALK demonstrates a strong interaction between ceritinib and the P-loop which is facilitated by T1151 on the β3 sheet, a feature not present in the alectinib/ALK or lorlatinib/ALK co-crystal structure.
explanation: Co-crystal structures explain differential sensitivity of ALK resistance mutations to different inhibitors, supporting the ALK-dependent resistance mechanism.
- reference: PMID:35085771
reference_title: EML4-ALK G1202R mutation induces EMT and confers resistance to ceritinib in NSCLC cells via activation of STAT3/Slug signaling.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: induced an epithelial-mesenchymal transition (EMT)
explanation: Supports EMT as a cellular phenotype linked to ALK G1202R-mediated TKI resistance.
- reference: PMID:41433419
reference_title: Cancer-associated fibroblasts confer ALK inhibitor resistance in EML4-ALK-driven lung cancer by concurrent integrin and MET signaling.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Concurrent targeting of MET and integrin
explanation: Supports HGF-MET and integrin signaling from CAF coculture as ALK inhibitor resistance pathways.
- reference: PMID:38521003
reference_title: Concurrent inhibition of ALK and SRC kinases disrupts the ALK lung tumor cell proteome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Co-targeting of ALK and SRC showed remarkable inhibitory effects
explanation: Supports SRC activation as a bypass targetable with ALK inhibition in ALK-driven lung tumor models.
- reference: CIVIC_EID:441
reference_title: "EML4::ALK Fusion AND ALK G1202R / Lung Non-small Cell Carcinoma (Predictive Resistance)"
supports: SUPPORT
evidence_source: OTHER
snippet: The G1202R mutation in the EML4-ALK fusion was found to confer resistance to crizotinib in Ba/F3 cells.
explanation: CIViC's accepted evidence item supports ALK G1202R as an ALK-dependent crizotinib resistance mechanism.
pdb_structures:
- pdb_id: 2XP2
description: Crizotinib bound to wild-type ALK kinase domain (RCSB title "Structure of the Human Anaplastic Lymphoma Kinase in Complex with Crizotinib") — G1202R solvent-front mutation sterically clashes with the crizotinib piperidine ring, explaining first-generation resistance. Note 2WGJ is the c-Met/crizotinib co-crystal from the same paper.
method: X-ray
resolution_angstrom: 1.86
ligand: crizotinib
target_protein: ALK kinase domain (wild-type reference for resistance mapping)
publication: PMID:21575866
- pdb_id: 4CLI
description: Lorlatinib/ALK co-crystal — macrocyclic scaffold maintains binding despite G1202R due to compact shape that avoids the solvent-front clash
method: X-ray
resolution_angstrom: 1.65
ligand: lorlatinib
target_protein: ALK kinase domain
biological_processes:
- preferred_term: response to drug
modifier: ABNORMAL
term:
id: GO:0009410
label: response to xenobiotic stimulus
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: Neoplastic
name: Lung Adenocarcinoma
frequency: VERY_FREQUENT
description: >-
ALK-rearranged NSCLC is almost exclusively adenocarcinoma histology, often
with signet ring or cribriform patterns. Typically presents in younger
patients.
phenotype_term:
preferred_term: Lung adenocarcinoma
term:
id: HP:0030078
label: Lung adenocarcinoma
evidence:
- reference: DOI:10.1177/03008916231202149
reference_title: "ALK-rearranged lung adenocarcinoma: From molecular genetics to therapeutic targeting"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Anaplastic Lymphoma Kinase (ALK) is a potent oncogenic driver of lung adenocarcinoma (LUAD).
explanation: Confirms lung adenocarcinoma as the histologic context for ALK-rearranged tumors.
- category: Clinical
name: Young Age at Diagnosis
frequency: VERY_FREQUENT
description: >-
ALK fusion is enriched in younger lung cancer patients. This reflects a
driver-fusion carcinogenic pathway rather than a classic smoking-related
mutation burden pattern.
phenotype_term:
preferred_term: Neoplasm of the lung
term:
id: HP:0100526
label: Neoplasm of the lung
evidence:
- reference: PMID:37007097
reference_title: "Association of smoking and ALK tyrosine-kinase inhibitors on overall survival in treatment-naïve ALK-positive advanced lung adenocarcinoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Anaplastic lymphoma kinase (ALK) fusion mutation is more common in younger and never-smoking lung cancer patients.
explanation: Directly supports younger age enrichment in ALK fusion-positive lung cancer.
- category: Clinical
name: Never/Light Smoker
frequency: VERY_FREQUENT
description: >-
Like EGFR-mutant NSCLC, ALK-rearranged tumors occur predominantly in
never-smokers or light smokers.
phenotype_term:
preferred_term: Neoplasm of the lung
term:
id: HP:0100526
label: Neoplasm of the lung
evidence:
- reference: PMID:37007097
reference_title: "Association of smoking and ALK tyrosine-kinase inhibitors on overall survival in treatment-naïve ALK-positive advanced lung adenocarcinoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 179 (27.5) smokers, 461 (70.9%) never-smokers, 10 (1.5%) with unknown smoking status
explanation: In a real-world cohort of ALK-positive advanced lung adenocarcinoma, most patients with known smoking status were never-smokers.
- category: Clinical
name: Brain Metastases
frequency: FREQUENT
description: >-
Brain metastases are a frequent manifestation of ALK-translocated NSCLC.
CNS-active ALK TKIs such as alectinib, brigatinib, and lorlatinib are
important because modern ALK inhibitors can prevent and treat intracranial
disease.
phenotype_term:
preferred_term: Neoplasm of the nervous system
term:
id: HP:0004375
label: Neoplasm of the nervous system
evidence:
- reference: PMID:34147645
reference_title: "Treatment of brain metastases in ALK-positive non-small cell lung cancer."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Brain metastases are quite frequent in patients with ALK-translocated non-small cell lung cancer (NSCLC)"
explanation: Directly supports brain metastases as a frequent clinical manifestation of ALK-translocated NSCLC.
- reference: PMID:40024442
reference_title: "First-Line Lorlatinib Versus Crizotinib in Asian Patients With Advanced ALK-Positive NSCLC: Five-Year Outcomes From the CROWN Study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: the intracranial objective response rate was 69%
explanation: Five-year CROWN subgroup data support strong intracranial activity for first-line lorlatinib in patients with baseline brain metastases.
- reference: PMID:38598794
reference_title: Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: clinically meaningful benefit with respect to CNS disease-free
explanation: ALINA supports CNS disease-free survival benefit with adjuvant alectinib versus chemotherapy.
biochemical:
- name: ALK Testing
notes: >-
ALK testing is required for all advanced non-squamous NSCLC. Methods include
FISH (FDA-approved companion diagnostic), immunohistochemistry (screening),
and next-generation sequencing (identifies fusion partner and variant).
ALK is mutually exclusive with EGFR mutations.
evidence:
- reference: DOI:10.3390/biomedicines12020297
reference_title: "Unraveling the Potential of ALK-Targeted Therapies in Non-Small Cell Lung Cancer: Comprehensive Insights and Future Directions"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: the review explores innovative directions such as ALK molecular diagnostics
explanation: Comprehensive review highlights the central role of ALK molecular diagnostics in identifying eligible NSCLC patients.
genetic:
- name: ALK
association: Somatic Rearrangement
inheritance:
- name: Somatic
evidence:
- reference: PMID:27637426
reference_title: "ALK alterations and inhibition in lung cancer."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: the discovery of NSCLC driven by activating rearrangements of the anaplastic lymphoma kinase (ALK) gene
explanation: ALK rearrangements in NSCLC are somatic genomic events acquired in tumor cells, not germline.
notes: >-
ALK (2p23.2) encodes anaplastic lymphoma kinase, a receptor tyrosine kinase.
Gene rearrangements occur somatically and are not inherited. EML4-ALK is a
common fusion resulting from inv(2)(p21;p23). Resistance mutations include
L1196M (gatekeeper), G1202R (solvent front), and compound mutations.
evidence:
- reference: PMID:27637426
reference_title: "ALK alterations and inhibition in lung cancer."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: the discovery of NSCLC driven by activating rearrangements of the anaplastic lymphoma kinase (ALK) gene
explanation: Establishes ALK gene rearrangements as the defining genetic lesion of this NSCLC subset.
- reference: CIVIC_ASSERTION:3
reference_title: "v::ALK Fusion / Lung Non-small Cell Carcinoma (Predictive Sensitivity/Response)"
supports: SUPPORT
evidence_source: OTHER
snippet: ALK-FUSIONS are found in 3-5% of non-small cell lung cancer and act as a targetable driver mutation.
explanation: CIViC's accepted assertion supports ALK fusions as defining, targetable genetic drivers in NSCLC.
- name: EML4
association: Fusion Partner
inheritance:
- name: Somatic
evidence:
- reference: DOI:10.1177/03008916231202149
reference_title: "ALK-rearranged lung adenocarcinoma: From molecular genetics to therapeutic targeting"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: ALK is constitutively activated by gene fusion events between the ALK and other gene fusion partners in about 2-3% of LUADs
explanation: Fusion gene events are somatic genomic rearrangements in tumor cells.
notes: >-
EML4 (2p21) encodes echinoderm microtubule-associated protein-like 4.
Provides the N-terminus and dimerization domain in EML4-ALK fusions.
Multiple fusion variants exist based on EML4 breakpoint (V1-V8).
evidence:
- reference: DOI:10.1177/03008916231202149
reference_title: "ALK-rearranged lung adenocarcinoma: From molecular genetics to therapeutic targeting"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: ALK is constitutively activated by gene fusion events between the ALK and other gene fusion partners in about 2-3% of LUADs
explanation: Supports EML4 (and other partners) as the fusion partner that drives constitutive ALK activation.
treatments:
- name: Alectinib
description: >-
Second-generation ALK TKI with excellent CNS penetration. First-line standard
of care based on ALEX trial showing superior PFS and OS vs crizotinib, and an
adjuvant option for resected ALK-positive NSCLC based on ALINA. Active
against many crizotinib-resistant mutations.
pdb_structures:
- pdb_id: 3AOX
description: Alectinib bound to the ALK kinase domain, revealing the unique binding mode that confers activity against crizotinib-resistant gatekeeper mutations
resolution_angstrom: 1.7
method: X-ray
ligand: alectinib
target_protein: ALK (anaplastic lymphoma kinase)
publication: PMID:21575866
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: alectinib
term:
id: CHEBI:90936
label: alectinib
evidence:
- reference: DOI:10.3390/biomedicines12020297
reference_title: "Unraveling the Potential of ALK-Targeted Therapies in Non-Small Cell Lung Cancer: Comprehensive Insights and Future Directions"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "second-generation TKIs such as alectinib, ceritinib, and brigatinib have emerged to address resistance issues initially associated with the pioneer ALK-TKI, crizotinib"
explanation: Establishes alectinib as a second-generation ALK TKI used to address crizotinib resistance.
- reference: PMID:38598794
reference_title: Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: adjuvant alectinib significantly improved disease-free survival
explanation: ALINA supports alectinib as adjuvant therapy after resection of stage IB-IIIA ALK-positive NSCLC.
- reference: CIVIC_ASSERTION:34
reference_title: "v::ALK Fusion / Lung Non-small Cell Carcinoma (Predictive Sensitivity/Response)"
supports: SUPPORT
evidence_source: OTHER
snippet: ALK fusion positive NSCLC is sensitive to alectinib
explanation: CIViC's accepted assertion directly supports alectinib sensitivity in ALK fusion-positive NSCLC.
- name: Lorlatinib
description: >-
Third-generation ALK TKI designed to overcome resistance mutations including
G1202R. Excellent CNS activity. Can be used first-line based on CROWN, where
five-year follow-up showed durable PFS advantage over crizotinib, or after
progression on prior ALK TKIs.
pdb_structures:
- pdb_id: 4CLI
description: Lorlatinib bound to the ALK kinase domain, showing the macrocyclic scaffold that maintains binding despite the G1202R solvent-front resistance mutation
resolution_angstrom: 1.65
method: X-ray
ligand: lorlatinib
target_protein: ALK (anaplastic lymphoma kinase)
publication: PMID:24900437
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: lorlatinib
term:
id: CHEBI:143117
label: lorlatinib
evidence:
- reference: PMID:28676215
reference_title: "Identification of a novel T1151K ALK mutation in a patient with ALK-rearranged NSCLC with prior exposure to crizotinib and ceritinib."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: a feature not present in the alectinib/ALK or lorlatinib/ALK co-crystal structure
explanation: Co-crystal structures of lorlatinib/ALK demonstrate the binding mode that overcomes resistance mutations like T1151K and G1202R.
- reference: PMID:40024442
reference_title: "First-Line Lorlatinib Versus Crizotinib in Asian Patients With Advanced ALK-Positive NSCLC: Five-Year Outcomes From the CROWN Study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: the five-year PFS was 63%
explanation: Five-year CROWN subgroup data support durable first-line lorlatinib benefit over crizotinib.
- name: Ceritinib
description: >-
Second-generation ALK TKI used in ALK-positive NSCLC, including settings
where resistance to crizotinib is a concern. It is less favored than newer
CNS-active ALK inhibitors in many current sequencing strategies but remains
part of the ALK inhibitor class history.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: ceritinib
term:
id: CHEBI:78432
label: ceritinib
evidence:
- reference: DOI:10.3390/biomedicines12020297
reference_title: "Unraveling the Potential of ALK-Targeted Therapies in Non-Small Cell Lung Cancer: Comprehensive Insights and Future Directions"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "second-generation TKIs such as alectinib, ceritinib, and brigatinib have emerged to address resistance issues initially associated with the pioneer ALK-TKI, crizotinib"
explanation: Directly identifies ceritinib as a second-generation ALK TKI used to address resistance issues after crizotinib.
- name: Brigatinib
description: >-
Second-generation ALK TKI with broad activity against resistance mutations
and good CNS penetration. Alternative to alectinib in first-line or
subsequent settings.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: brigatinib
term:
id: CHEBI:232810
label: brigatinib
evidence:
- reference: DOI:10.3390/biomedicines12020297
reference_title: "Unraveling the Potential of ALK-Targeted Therapies in Non-Small Cell Lung Cancer: Comprehensive Insights and Future Directions"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "second-generation TKIs such as alectinib, ceritinib, and brigatinib have emerged to address resistance issues initially associated with the pioneer ALK-TKI, crizotinib"
explanation: Establishes brigatinib among the second-generation ALK TKIs used to address crizotinib resistance.
- name: Crizotinib
description: >-
First-generation ALK TKI that established proof-of-concept for ALK
inhibition in lung cancer. Now largely replaced by more potent second/third
generation agents due to lower CNS efficacy and resistance.
pdb_structures:
- pdb_id: 2XP2
description: Crizotinib bound to wild-type ALK kinase domain (RCSB title "Structure of the Human Anaplastic Lymphoma Kinase in Complex with Crizotinib"), showing the aminopyridine scaffold inserted into the ATP-binding cleft. Note 2WGJ is the c-Met/crizotinib co-crystal from the same paper.
resolution_angstrom: 1.86
method: X-ray
ligand: crizotinib
target_protein: ALK (anaplastic lymphoma kinase)
publication: PMID:21575866
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: crizotinib
term:
id: CHEBI:64310
label: crizotinib
evidence:
- reference: PMID:23805942
reference_title: "The preclinical profile of crizotinib for the treatment of non-small-cell lung cancer and other neoplastic disorders."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: The article highlights its beginning with the X-ray crystallographic structure of a lead compound (PHA-0665752) bound to the active site of the kinase domain of c-Met.
explanation: Preclinical structural biology directly enabled the discovery and development of crizotinib as the first ALK TKI for NSCLC.
- reference: CIVIC_ASSERTION:3
reference_title: "v::ALK Fusion / Lung Non-small Cell Carcinoma (Predictive Sensitivity/Response)"
supports: SUPPORT
evidence_source: OTHER
snippet: Lung adenocarcinoma positive for ALK-FUSIONS have been found to be sensitive to crizotinib treatment
explanation: CIViC's accepted assertion directly supports crizotinib sensitivity in ALK fusion-positive NSCLC.
- name: Chemotherapy
description: >-
Pemetrexed-based chemotherapy, including platinum/pemetrexed regimens, is a
cytotoxic treatment option in advanced ALK-positive NSCLC when targeted
therapy options are exhausted or unavailable.
treatment_term:
preferred_term: chemotherapy
term:
id: MAXO:0000647
label: chemotherapy
evidence:
- reference: PMID:22887466
reference_title: "Pemetrexed-based chemotherapy in patients with advanced, ALK-positive non-small cell lung cancer."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Among 70 ALK-positive patients treated with a platinum/pemetrexed regimen, the median PFS (mPFS) was 7.3 months
explanation: Directly supports platinum/pemetrexed chemotherapy as a studied regimen in advanced ALK-positive NSCLC.
computational_models:
- name: ALK Kinase Domain Crystal Structure-Guided Drug Design
description: >-
X-ray crystallographic structures of lead compounds bound to the kinase domain
of c-Met/ALK were instrumental in the structure-based development of crizotinib,
the first FDA-approved ALK inhibitor for EML4-ALK-positive NSCLC. Crystal structures
guided optimization of lipophilic efficiency and target binding, and continue
to
inform development of next-generation ALK inhibitors (ceritinib, alectinib, lorlatinib)
that overcome resistance mutations.
model_type: STRUCTURAL_PREDICTION
publication: PMID:23805942
findings:
- statement: X-ray crystallographic structure of a lead compound bound to c-Met kinase domain guided development of crizotinib
- statement: Co-crystal structures of ALK with different inhibitors explain resistance mutation profiles
evidence:
- reference: PMID:23805942
reference_title: "The preclinical profile of crizotinib for the treatment of non-small-cell lung cancer and other neoplastic disorders."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The article highlights its beginning with the X-ray crystallographic structure of a lead compound (PHA-0665752) bound to the active site of the kinase domain of c-Met."
explanation: Demonstrates that structural biology directly guided the drug discovery process for the first ALK inhibitor crizotinib.
- reference: PMID:28676215
reference_title: "Identification of a novel T1151K ALK mutation in a patient with ALK-rearranged NSCLC with prior exposure to crizotinib and ceritinib."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The co-crystal structure of ceritinib/ALK demonstrates a strong interaction between ceritinib and the P-loop which is facilitated by T1151 on the β3 sheet, a feature not present in the alectinib/ALK or lorlatinib/ALK co-crystal structure."
explanation: Co-crystal structures explain differential sensitivity of ALK resistance mutations to different inhibitors.
disease_term:
preferred_term: lung adenocarcinoma
term:
id: MONDO:0005061
label: lung adenocarcinoma

classifications:
icdo_morphology:
classification_value: Carcinoma
harrisons_chapter:
- classification_value: cancer
- classification_value: solid tumor
references:
- reference: DOI:10.1177/03008916231202149
title: 'Alk-rearranged lung adenocarcinoma: From molecular genetics to therapeutic targeting'
findings:
- statement: Anaplastic Lymphoma Kinase (ALK) is a potent oncogenic driver of lung adenocarcinoma (LUAD).
supporting_text: Anaplastic Lymphoma Kinase (ALK) is a potent oncogenic driver of lung adenocarcinoma (LUAD).
evidence:
- reference: DOI:10.1177/03008916231202149
reference_title: 'Alk-rearranged lung adenocarcinoma: From molecular genetics to therapeutic targeting'
supports: SUPPORT
evidence_source: OTHER
snippet: Anaplastic Lymphoma Kinase (ALK) is a potent oncogenic driver of lung adenocarcinoma (LUAD).
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
found_in:
- ALK_Rearranged_NSCLC-deep-research-cyberian-codex.md
- ALK_Rearranged_NSCLC-deep-research-falcon.md
- reference: DOI:10.3389/fimmu.2025.1515748
title: 'Non-small cell lung cancer and the tumor microenvironment: making headway from targeted therapies to advanced immunotherapy'
findings:
- statement: 'Non-small cell lung cancer and the tumor microenvironment: making headway from targeted therapies to advanced immunotherapy'
supporting_text: Over the past decades, significant progress has been made in the understanding of non-small cell lung cancer (NSCLC) biology and tumor progression mechanisms, resulting in the development of novel strategies for early detection and wide-ranging care approaches.
evidence:
- reference: DOI:10.3389/fimmu.2025.1515748
reference_title: 'Non-small cell lung cancer and the tumor microenvironment: making headway from targeted therapies to advanced immunotherapy'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Over the past decades, significant progress has been made in the understanding of non-small cell lung cancer (NSCLC) biology and tumor progression mechanisms, resulting in the development of novel strategies for early detection and wide-ranging care approaches.
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
found_in:
- ALK_Rearranged_NSCLC-deep-research-cyberian-codex.md
- ALK_Rearranged_NSCLC-deep-research-falcon.md
- reference: DOI:10.3390/biomedicines12020297
title: 'Unraveling the Potential of ALK-Targeted Therapies in Non-Small Cell Lung Cancer: Comprehensive Insights and Future Directions'
findings:
- statement: 'and Objective: This review comprehensively explores the intricate landscape of anaplastic lymphoma kinase (ALK), focusing specifically on its pivotal role in non-small cell lung cancer (NSCLC).'
supporting_text: 'and Objective: This review comprehensively explores the intricate landscape of anaplastic lymphoma kinase (ALK), focusing specifically on its pivotal role in non-small cell lung cancer (NSCLC).'
evidence:
- reference: DOI:10.3390/biomedicines12020297
reference_title: 'Unraveling the Potential of ALK-Targeted Therapies in Non-Small Cell Lung Cancer: Comprehensive Insights and Future Directions'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'and Objective: This review comprehensively explores the intricate landscape of anaplastic lymphoma kinase (ALK), focusing specifically on its pivotal role in non-small cell lung cancer (NSCLC).'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
found_in:
- ALK_Rearranged_NSCLC-deep-research-cyberian-codex.md
- ALK_Rearranged_NSCLC-deep-research-falcon.md
- reference: DOI:10.3390/ijms26010308
title: 'EML4-ALK: Update on ALK Inhibitors'
findings:
- statement: 'EML4-ALK: Update on ALK Inhibitors'
supporting_text: Since the discovery of the first-generation ALK inhibitor, many other tyrosine kinase inhibitors have been demonstrated to be effective in the first line or further lines of treatment in patients with advanced non-small cell lung cancer with EMLA4-ALK translocation.
evidence:
- reference: DOI:10.3390/ijms26010308
reference_title: 'EML4-ALK: Update on ALK Inhibitors'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Since the discovery of the first-generation ALK inhibitor, many other tyrosine kinase inhibitors have been demonstrated to be effective in the first line or further lines of treatment in patients with advanced non-small cell lung cancer with EMLA4-ALK translocation.
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
found_in:
- ALK_Rearranged_NSCLC-deep-research-cyberian-codex.md
- ALK_Rearranged_NSCLC-deep-research-falcon.md
- reference: PMID:22887466
title: 'Pemetrexed-based chemotherapy in patients with advanced, ALK-positive non-small cell lung cancer.'
findings: []
- reference: PMID:34147645
title: 'Treatment of brain metastases in ALK-positive non-small cell lung cancer.'
findings: []
- reference: PMID:37007097
title: 'Association of smoking and ALK tyrosine-kinase inhibitors on overall survival in treatment-naïve ALK-positive advanced lung adenocarcinoma.'
findings: []
- reference: PMID:17625570
title: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2007 Aug 2;448(7153):561-6. doi: 10.1038/nature05945.'
supporting_text: '2007 Aug 2;448(7153):561-6. doi: 10.1038/nature05945.'
evidence:
- reference: PMID:17625570
reference_title: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2007 Aug 2;448(7153):561-6. doi: 10.1038/nature05945.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:20952506
title: Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2010 Dec 1;70(23):9827-36. doi: 10.1158/0008-5472.CAN-10-1671.'
supporting_text: '2010 Dec 1;70(23):9827-36. doi: 10.1158/0008-5472.CAN-10-1671.'
evidence:
- reference: PMID:20952506
reference_title: Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene.
supports: SUPPORT
evidence_source: OTHER
snippet: '2010 Dec 1;70(23):9827-36. doi: 10.1158/0008-5472.CAN-10-1671.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:22129856
title: 'Clinicopathologic implication of ALK rearrangement in surgically resected lung cancer: a proposal of diagnostic algorithm for ALK-rearranged adenocarcinoma.'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: To characterize the clinicopathologic features of ALK-rearranged lung cancer, and suggest a molecular test protocol for lung adenocarcinoma in the small biopsy specimen.
supporting_text: To characterize the clinicopathologic features of ALK-rearranged lung cancer, and suggest a molecular test protocol for lung adenocarcinoma in the small biopsy specimen.
evidence:
- reference: PMID:22129856
reference_title: 'Clinicopathologic implication of ALK rearrangement in surgically resected lung cancer: a proposal of diagnostic algorithm for ALK-rearranged adenocarcinoma.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: To characterize the clinicopathologic features of ALK-rearranged lung cancer, and suggest a molecular test protocol for lung adenocarcinoma in the small biopsy specimen.
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:24199682
title: Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the tyrosine kinase inhibitor crizotinib in ALK rearranged lung cancer.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2014 Jan;83(1):37-43. doi: 10.1016/j.lungcan.2013.09.019.'
supporting_text: '2014 Jan;83(1):37-43. doi: 10.1016/j.lungcan.2013.09.019.'
evidence:
- reference: PMID:24199682
reference_title: Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the tyrosine kinase inhibitor crizotinib in ALK rearranged lung cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: '2014 Jan;83(1):37-43. doi: 10.1016/j.lungcan.2013.09.019.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:24290361
title: A novel ALK rearrangement in an inflammatory myofibroblastic tumor in a neonate.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2013 Sep-Oct;206(9-10):353-6. doi: 10.1016/j.cancergen.2013.10.002.'
supporting_text: '2013 Sep-Oct;206(9-10):353-6. doi: 10.1016/j.cancergen.2013.10.002.'
evidence:
- reference: PMID:24290361
reference_title: A novel ALK rearrangement in an inflammatory myofibroblastic tumor in a neonate.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2013 Sep-Oct;206(9-10):353-6. doi: 10.1016/j.cancergen.2013.10.002.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:24419060
title: The selective anaplastic lymphoma receptor tyrosine kinase inhibitor ASP3026 induces tumor regression and prolongs survival in non-small cell lung cancer model mice.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2014 Feb;13(2):329-40. doi: 10.1158/1535-7163.MCT-13-0395.'
supporting_text: '2014 Feb;13(2):329-40. doi: 10.1158/1535-7163.MCT-13-0395.'
evidence:
- reference: PMID:24419060
reference_title: The selective anaplastic lymphoma receptor tyrosine kinase inhibitor ASP3026 induces tumor regression and prolongs survival in non-small cell lung cancer model mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: '2014 Feb;13(2):329-40. doi: 10.1158/1535-7163.MCT-13-0395.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:25813151
title: The clinicopathological significance of ALK rearrangements and KRAS and EGFR mutations in primary pulmonary mucinous adenocarcinoma.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2015 Aug;36(8):6417-24. doi: 10.1007/s13277-015-3331-4.'
supporting_text: '2015 Aug;36(8):6417-24. doi: 10.1007/s13277-015-3331-4.'
evidence:
- reference: PMID:25813151
reference_title: The clinicopathological significance of ALK rearrangements and KRAS and EGFR mutations in primary pulmonary mucinous adenocarcinoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2015 Aug;36(8):6417-24. doi: 10.1007/s13277-015-3331-4.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:26095438
title: Analysis of Histologic Features Suspecting Anaplastic Lymphoma Kinase (ALK)-Expressing Pulmonary Adenocarcinoma.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Analysis of Histologic Features Suspecting Anaplastic Lymphoma Kinase (ALK)-Expressing Pulmonary Adenocarcinoma
supporting_text: Since 2007 when anaplastic lymphoma kinase (ALK) rearrangements were discovered in non-small cell lung cancer, the ALK gene has received attention due to ALK-targeted therapy, and a notable treatment advantage has been observed in patients harboring the EML4/ALK translocation.
evidence:
- reference: PMID:26095438
reference_title: Analysis of Histologic Features Suspecting Anaplastic Lymphoma Kinase (ALK)-Expressing Pulmonary Adenocarcinoma.
supports: SUPPORT
evidence_source: OTHER
snippet: Since 2007 when anaplastic lymphoma kinase (ALK) rearrangements were discovered in non-small cell lung cancer, the ALK gene has received attention due to ALK-targeted therapy, and a notable treatment advantage has been observed in patients harboring the EML4/ALK translocation.
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:26536196
title: Clinical Implications of Variant ALK FISH Rearrangement Patterns.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2015 Nov;10(11):1648-52. doi: 10.1097/JTO.0000000000000665.'
supporting_text: '2015 Nov;10(11):1648-52. doi: 10.1097/JTO.0000000000000665.'
evidence:
- reference: PMID:26536196
reference_title: Clinical Implications of Variant ALK FISH Rearrangement Patterns.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2015 Nov;10(11):1648-52. doi: 10.1097/JTO.0000000000000665.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:27545757
title: Clinical Drug-Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2017 May;6(3):280-291. doi: 10.1002/cpdd.298.'
supporting_text: '2017 May;6(3):280-291. doi: 10.1002/cpdd.298.'
evidence:
- reference: PMID:27545757
reference_title: Clinical Drug-Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2017 May;6(3):280-291. doi: 10.1002/cpdd.298.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:27604320
title: Neuronal leucine-rich repeat 1 negatively regulates anaplastic lymphoma kinase in neuroblastoma.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2016 Sep 8;6:32682. doi: 10.1038/srep32682.'
supporting_text: '2016 Sep 8;6:32682. doi: 10.1038/srep32682.'
evidence:
- reference: PMID:27604320
reference_title: Neuronal leucine-rich repeat 1 negatively regulates anaplastic lymphoma kinase in neuroblastoma.
supports: SUPPORT
evidence_source: OTHER
snippet: '2016 Sep 8;6:32682. doi: 10.1038/srep32682.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:30008631
title: Radon Exposure-induced Genetic Variations in Lung Cancers among Never Smokers.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Lung cancer in never smokers (LCINS) differs etiologically and clinically from lung cancer attributed to smoking.
supporting_text: Lung cancer in never smokers (LCINS) differs etiologically and clinically from lung cancer attributed to smoking.
evidence:
- reference: PMID:30008631
reference_title: Radon Exposure-induced Genetic Variations in Lung Cancers among Never Smokers.
supports: SUPPORT
evidence_source: OTHER
snippet: Lung cancer in never smokers (LCINS) differs etiologically and clinically from lung cancer attributed to smoking.
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:30255938
title: Identification of a highly lethal V3(+) TP53(+) subset in ALK(+) lung adenocarcinoma.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2019 Jan 1;144(1):190-199. doi: 10.1002/ijc.31893.'
supporting_text: '2019 Jan 1;144(1):190-199. doi: 10.1002/ijc.31893.'
evidence:
- reference: PMID:30255938
reference_title: Identification of a highly lethal V3(+) TP53(+) subset in ALK(+) lung adenocarcinoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2019 Jan 1;144(1):190-199. doi: 10.1002/ijc.31893.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:30599201
title: Natural History and Factors Associated with Overall Survival in Stage IV ALK-Rearranged Non-Small Cell Lung Cancer.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2019 Apr;14(4):691-700. doi: 10.1016/j.jtho.2018.12.014.'
supporting_text: '2019 Apr;14(4):691-700. doi: 10.1016/j.jtho.2018.12.014.'
evidence:
- reference: PMID:30599201
reference_title: Natural History and Factors Associated with Overall Survival in Stage IV ALK-Rearranged Non-Small Cell Lung Cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: '2019 Apr;14(4):691-700. doi: 10.1016/j.jtho.2018.12.014.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:30642913
title: Immunotherapy for the First-Line Treatment of Patients with Metastatic Non-Small Cell Lung Cancer.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2019 May 1;25(9):2691-2698. doi: 10.1158/1078-0432.CCR-18-3904.'
supporting_text: '2019 May 1;25(9):2691-2698. doi: 10.1158/1078-0432.CCR-18-3904.'
evidence:
- reference: PMID:30642913
reference_title: Immunotherapy for the First-Line Treatment of Patients with Metastatic Non-Small Cell Lung Cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2019 May 1;25(9):2691-2698. doi: 10.1158/1078-0432.CCR-18-3904.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:30902613
title: Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-Positive Advanced Non-Small Cell Lung Cancer in the Global Phase III ALEX Study.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2019 Jul;14(7):1233-1243. doi: 10.1016/j.jtho.2019.03.007.'
supporting_text: '2019 Jul;14(7):1233-1243. doi: 10.1016/j.jtho.2019.03.007.'
evidence:
- reference: PMID:30902613
reference_title: Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-Positive Advanced Non-Small Cell Lung Cancer in the Global Phase III ALEX Study.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2019 Jul;14(7):1233-1243. doi: 10.1016/j.jtho.2019.03.007.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:30903971
title: 'Lung cancer and residential radon in never-smokers: A pooling study in the Northwest of Spain.'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Using a pooled case-control study design, including only never-smokers, we have assessed the association of residential radon exposure with the subsequent occurrence of lung cancer.
supporting_text: Using a pooled case-control study design, including only never-smokers, we have assessed the association of residential radon exposure with the subsequent occurrence of lung cancer.
evidence:
- reference: PMID:30903971
reference_title: 'Lung cancer and residential radon in never-smokers: A pooling study in the Northwest of Spain.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Using a pooled case-control study design, including only never-smokers, we have assessed the association of residential radon exposure with the subsequent occurrence of lung cancer.
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:30954906
title: 'Choosing wisely first line immunotherapy in non-small cell lung cancer (NSCLC): what to add and what to leave out.'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2019 May;75:39-51. doi: 10.1016/j.ctrv.2019.03.004.'
supporting_text: '2019 May;75:39-51. doi: 10.1016/j.ctrv.2019.03.004.'
evidence:
- reference: PMID:30954906
reference_title: 'Choosing wisely first line immunotherapy in non-small cell lung cancer (NSCLC): what to add and what to leave out.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2019 May;75:39-51. doi: 10.1016/j.ctrv.2019.03.004.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:31010758
title: '[Therapeutic options for oligoprogressive non-small cell lung cancer].'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2019 Apr;36(4):519-526. doi: 10.1016/j.rmr.2018.04.011.'
supporting_text: '2019 Apr;36(4):519-526. doi: 10.1016/j.rmr.2018.04.011.'
evidence:
- reference: PMID:31010758
reference_title: '[Therapeutic options for oligoprogressive non-small cell lung cancer].'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2019 Apr;36(4):519-526. doi: 10.1016/j.rmr.2018.04.011.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:31521978
title: The clinical responses of TNIP2-ALK fusion variants to crizotinib in ALK-rearranged lung adenocarcinoma.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2019 Nov;137:19-22. doi: 10.1016/j.lungcan.2019.08.032.'
supporting_text: '2019 Nov;137:19-22. doi: 10.1016/j.lungcan.2019.08.032.'
evidence:
- reference: PMID:31521978
reference_title: The clinical responses of TNIP2-ALK fusion variants to crizotinib in ALK-rearranged lung adenocarcinoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2019 Nov;137:19-22. doi: 10.1016/j.lungcan.2019.08.032.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:31630043
title: ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2019 Dec;138:13-18. doi: 10.1016/j.lungcan.2019.09.023.'
supporting_text: '2019 Dec;138:13-18. doi: 10.1016/j.lungcan.2019.09.023.'
evidence:
- reference: PMID:31630043
reference_title: ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2019 Dec;138:13-18. doi: 10.1016/j.lungcan.2019.09.023.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:31633304
title: Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK-rearranged lung cancer.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2019 Dec;11(12):e10581. doi: 10.15252/emmm.201910581.'
supporting_text: '2019 Dec;11(12):e10581. doi: 10.15252/emmm.201910581.'
evidence:
- reference: PMID:31633304
reference_title: Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK-rearranged lung cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: '2019 Dec;11(12):e10581. doi: 10.15252/emmm.201910581.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:31894386
title: Unique molecular features and clinical outcomes in young patients with non-small cell lung cancer harboring ALK fusion genes.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2020 Apr;146(4):935-944. doi: 10.1007/s00432-019-03116-6.'
supporting_text: '2020 Apr;146(4):935-944. doi: 10.1007/s00432-019-03116-6.'
evidence:
- reference: PMID:31894386
reference_title: Unique molecular features and clinical outcomes in young patients with non-small cell lung cancer harboring ALK fusion genes.
supports: SUPPORT
evidence_source: OTHER
snippet: '2020 Apr;146(4):935-944. doi: 10.1007/s00432-019-03116-6.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:32062313
title: 'Lung cancer in never smokers: The role of different risk factors other than tobacco smoking.'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2020 Apr;148:102895. doi: 10.1016/j.critrevonc.2020.102895.'
supporting_text: '2020 Apr;148:102895. doi: 10.1016/j.critrevonc.2020.102895.'
evidence:
- reference: PMID:32062313
reference_title: 'Lung cancer in never smokers: The role of different risk factors other than tobacco smoking.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2020 Apr;148:102895. doi: 10.1016/j.critrevonc.2020.102895.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:32409712
title: Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2020 May 14;11(1):2393. doi: 10.1038/s41467-020-16212-w.'
supporting_text: '2020 May 14;11(1):2393. doi: 10.1038/s41467-020-16212-w.'
evidence:
- reference: PMID:32409712
reference_title: Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures.
supports: SUPPORT
evidence_source: OTHER
snippet: '2020 May 14;11(1):2393. doi: 10.1038/s41467-020-16212-w.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:32482786
title: Low-dose chest computed tomographic screening and invasive diagnosis of pulmonary nodules for lung cancer in never-smokers.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Although lung cancer screening using low-dose computed tomography (LDCT) is now widely used in clinical practice, the characteristics and outcomes of diagnostic procedures related to screen-detected nodules in never-smokers remain unclear.
supporting_text: Although lung cancer screening using low-dose computed tomography (LDCT) is now widely used in clinical practice, the characteristics and outcomes of diagnostic procedures related to screen-detected nodules in never-smokers remain unclear.
evidence:
- reference: PMID:32482786
reference_title: Low-dose chest computed tomographic screening and invasive diagnosis of pulmonary nodules for lung cancer in never-smokers.
supports: SUPPORT
evidence_source: OTHER
snippet: Although lung cancer screening using low-dose computed tomography (LDCT) is now widely used in clinical practice, the characteristics and outcomes of diagnostic procedures related to screen-detected nodules in never-smokers remain unclear.
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:33222380
title: Pharmacoenhancement of Low Crizotinib Plasma Concentrations in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer using the CYP3A Inhibitor Cobicistat.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2021 Mar;14(2):487-491. doi: 10.1111/cts.12921.'
supporting_text: '2021 Mar;14(2):487-491. doi: 10.1111/cts.12921.'
evidence:
- reference: PMID:33222380
reference_title: Pharmacoenhancement of Low Crizotinib Plasma Concentrations in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer using the CYP3A Inhibitor Cobicistat.
supports: SUPPORT
evidence_source: OTHER
snippet: '2021 Mar;14(2):487-491. doi: 10.1111/cts.12921.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:33655698
title: Integration of comprehensive genomic profiling, tumor mutational burden, and PD-L1 expression to identify novel biomarkers of immunotherapy in non-small cell lung cancer.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2021 Apr;10(7):2216-2231. doi: 10.1002/cam4.3649.'
supporting_text: '2021 Apr;10(7):2216-2231. doi: 10.1002/cam4.3649.'
evidence:
- reference: PMID:33655698
reference_title: Integration of comprehensive genomic profiling, tumor mutational burden, and PD-L1 expression to identify novel biomarkers of immunotherapy in non-small cell lung cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: '2021 Apr;10(7):2216-2231. doi: 10.1002/cam4.3649.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:33761896
title: EML4-ALK induces cellular senescence in mortal normal human cells and promotes anchorage-independent growth in hTERT-transduced normal human cells.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC).
supporting_text: Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC).
evidence:
- reference: PMID:33761896
reference_title: EML4-ALK induces cellular senescence in mortal normal human cells and promotes anchorage-independent growth in hTERT-transduced normal human cells.
supports: SUPPORT
evidence_source: OTHER
snippet: Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC).
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:34271921
title: Molecular characteristics and clinical outcomes of complex ALK rearrangements identified by next-generation sequencing in non-small cell lung cancers.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Complex kinase rearrangement, a mutational process involving one or two chromosomes with clustered rearrangement breakpoints, interferes with the accurate detection of kinase fusions by DNA-based next-generation sequencing (NGS).
supporting_text: Complex kinase rearrangement, a mutational process involving one or two chromosomes with clustered rearrangement breakpoints, interferes with the accurate detection of kinase fusions by DNA-based next-generation sequencing (NGS).
evidence:
- reference: PMID:34271921
reference_title: Molecular characteristics and clinical outcomes of complex ALK rearrangements identified by next-generation sequencing in non-small cell lung cancers.
supports: SUPPORT
evidence_source: OTHER
snippet: Complex kinase rearrangement, a mutational process involving one or two chromosomes with clustered rearrangement breakpoints, interferes with the accurate detection of kinase fusions by DNA-based next-generation sequencing (NGS).
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:34626839
title: Deep RNA Sequencing Revealed Fusion Junctional Heterogeneity May Predict Crizotinib Treatment Efficacy in ALK-Rearranged NSCLC.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2022 Feb;17(2):264-276. doi: 10.1016/j.jtho.2021.09.016.'
supporting_text: '2022 Feb;17(2):264-276. doi: 10.1016/j.jtho.2021.09.016.'
evidence:
- reference: PMID:34626839
reference_title: Deep RNA Sequencing Revealed Fusion Junctional Heterogeneity May Predict Crizotinib Treatment Efficacy in ALK-Rearranged NSCLC.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2022 Feb;17(2):264-276. doi: 10.1016/j.jtho.2021.09.016.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:34661367
title: Phase-separated foci of EML4-ALK facilitate signalling and depend upon an active kinase conformation.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2021 Dec 6;22(12):e53693. doi: 10.15252/embr.202153693.'
supporting_text: '2021 Dec 6;22(12):e53693. doi: 10.15252/embr.202153693.'
evidence:
- reference: PMID:34661367
reference_title: Phase-separated foci of EML4-ALK facilitate signalling and depend upon an active kinase conformation.
supports: SUPPORT
evidence_source: OTHER
snippet: '2021 Dec 6;22(12):e53693. doi: 10.15252/embr.202153693.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:34994987
title: Targeted therapy for advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Targeted therapies directed at specific driver oncogenes have improved outcomes for individuals with advanced non-small cell lung cancer (NSCLC).
supporting_text: Targeted therapies directed at specific driver oncogenes have improved outcomes for individuals with advanced non-small cell lung cancer (NSCLC).
evidence:
- reference: PMID:34994987
reference_title: Targeted therapy for advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: Targeted therapies directed at specific driver oncogenes have improved outcomes for individuals with advanced non-small cell lung cancer (NSCLC).
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:35025076
title: 'Psychiatric Adverse Reactions to Anaplastic Lymphoma Kinase Inhibitors in Non-Small-Cell Lung Cancer: Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System.'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: The development of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) has improved the survival outcomes of patients with advanced ALK-rearranged non-small-cell lung cancer (NSCLC).
supporting_text: The development of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) has improved the survival outcomes of patients with advanced ALK-rearranged non-small-cell lung cancer (NSCLC).
evidence:
- reference: PMID:35025076
reference_title: 'Psychiatric Adverse Reactions to Anaplastic Lymphoma Kinase Inhibitors in Non-Small-Cell Lung Cancer: Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System.'
supports: SUPPORT
evidence_source: OTHER
snippet: The development of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) has improved the survival outcomes of patients with advanced ALK-rearranged non-small-cell lung cancer (NSCLC).
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:35085771
title: EML4-ALK G1202R mutation induces EMT and confers resistance to ceritinib in NSCLC cells via activation of STAT3/Slug signaling.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2022 Apr;92:110264. doi: 10.1016/j.cellsig.2022.110264.'
supporting_text: '2022 Apr;92:110264. doi: 10.1016/j.cellsig.2022.110264.'
evidence:
- reference: PMID:35085771
reference_title: EML4-ALK G1202R mutation induces EMT and confers resistance to ceritinib in NSCLC cells via activation of STAT3/Slug signaling.
supports: SUPPORT
evidence_source: OTHER
snippet: '2022 Apr;92:110264. doi: 10.1016/j.cellsig.2022.110264.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:35598361
title: The regulation of CD73 in non-small cell lung cancer.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Lung cancer is the leading cause of global cancer-related mortality.
supporting_text: Lung cancer is the leading cause of global cancer-related mortality.
evidence:
- reference: PMID:35598361
reference_title: The regulation of CD73 in non-small cell lung cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: Lung cancer is the leading cause of global cancer-related mortality.
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:35624360
title: Detecting anaplastic lymphoma kinase (ALK) gene rearrangements with next-generation sequencing remains a reliable approach in patients with non-small-cell lung cancer.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2022 Sep;481(3):405-419. doi: 10.1007/s00428-022-03339-y.'
supporting_text: '2022 Sep;481(3):405-419. doi: 10.1007/s00428-022-03339-y.'
evidence:
- reference: PMID:35624360
reference_title: Detecting anaplastic lymphoma kinase (ALK) gene rearrangements with next-generation sequencing remains a reliable approach in patients with non-small-cell lung cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2022 Sep;481(3):405-419. doi: 10.1007/s00428-022-03339-y.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:36270866
title: Real-World Treatment Sequencing, Toxicities, Health Utilities, and Survival Outcomes in Patients with Advanced ALK-Rearranged Non-Small-Cell Lung Cancer.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2023 Jan;24(1):40-50. doi: 10.1016/j.cllc.2022.09.007.'
supporting_text: '2023 Jan;24(1):40-50. doi: 10.1016/j.cllc.2022.09.007.'
evidence:
- reference: PMID:36270866
reference_title: Real-World Treatment Sequencing, Toxicities, Health Utilities, and Survival Outcomes in Patients with Advanced ALK-Rearranged Non-Small-Cell Lung Cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2023 Jan;24(1):40-50. doi: 10.1016/j.cllc.2022.09.007.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:37149843
title: 'EML4-ALK biology and drug resistance in non-small cell lung cancer: a new phase of discoveries.'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2023 Jun;17(6):950-963. doi: 10.1002/1878-0261.13446.'
supporting_text: '2023 Jun;17(6):950-963. doi: 10.1002/1878-0261.13446.'
evidence:
- reference: PMID:37149843
reference_title: 'EML4-ALK biology and drug resistance in non-small cell lung cancer: a new phase of discoveries.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2023 Jun;17(6):950-963. doi: 10.1002/1878-0261.13446.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:37190044
title: 'Gene Fusion Detection in NSCLC Routine Clinical Practice: Targeted-NGS or FISH?'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2023 Apr 11;12(8):1135. doi: 10.3390/cells12081135.'
supporting_text: '2023 Apr 11;12(8):1135. doi: 10.3390/cells12081135.'
evidence:
- reference: PMID:37190044
reference_title: 'Gene Fusion Detection in NSCLC Routine Clinical Practice: Targeted-NGS or FISH?'
supports: SUPPORT
evidence_source: OTHER
snippet: '2023 Apr 11;12(8):1135. doi: 10.3390/cells12081135.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:37597303
title: 'Comparative safety of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced anaplastic lymphoma kinase-mutated non-small cell lung cancer: Systematic review and network meta-analysis.'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2023 Oct;184:107319. doi: 10.1016/j.lungcan.2023.107319.'
supporting_text: '2023 Oct;184:107319. doi: 10.1016/j.lungcan.2023.107319.'
evidence:
- reference: PMID:37597303
reference_title: 'Comparative safety of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced anaplastic lymphoma kinase-mutated non-small cell lung cancer: Systematic review and network meta-analysis.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2023 Oct;184:107319. doi: 10.1016/j.lungcan.2023.107319.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:38042167
title: 'Low-dose CT screening among never-smokers with or without a family history of lung cancer in Taiwan: a prospective cohort study.'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis.
supporting_text: In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis.
evidence:
- reference: PMID:38042167
reference_title: 'Low-dose CT screening among never-smokers with or without a family history of lung cancer in Taiwan: a prospective cohort study.'
supports: SUPPORT
evidence_source: OTHER
snippet: In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis.
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:38521003
title: Concurrent inhibition of ALK and SRC kinases disrupts the ALK lung tumor cell proteome.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2024 May;74:101081. doi: 10.1016/j.drup.2024.101081.'
supporting_text: '2024 May;74:101081. doi: 10.1016/j.drup.2024.101081.'
evidence:
- reference: PMID:38521003
reference_title: Concurrent inhibition of ALK and SRC kinases disrupts the ALK lung tumor cell proteome.
supports: SUPPORT
evidence_source: OTHER
snippet: '2024 May;74:101081. doi: 10.1016/j.drup.2024.101081.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:38598794
title: Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non-small-cell lung cancer (NSCLC).
supporting_text: Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non-small-cell lung cancer (NSCLC).
evidence:
- reference: PMID:38598794
reference_title: Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non-small-cell lung cancer (NSCLC).
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:38904987
title: The Alk receptor tyrosine kinase regulates Sparkly, a novel activity regulating neuropeptide precursor in the Drosophila central nervous system.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2024 Jun 21;12:RP88985. doi: 10.7554/eLife.88985.'
supporting_text: '2024 Jun 21;12:RP88985. doi: 10.7554/eLife.88985.'
evidence:
- reference: PMID:38904987
reference_title: The Alk receptor tyrosine kinase regulates Sparkly, a novel activity regulating neuropeptide precursor in the Drosophila central nervous system.
supports: SUPPORT
evidence_source: OTHER
snippet: '2024 Jun 21;12:RP88985. doi: 10.7554/eLife.88985.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:38977146
title: 'Facing an un-met need in lung cancer screening: The never smokers.'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2024 Oct;202:104436. doi: 10.1016/j.critrevonc.2024.104436.'
supporting_text: '2024 Oct;202:104436. doi: 10.1016/j.critrevonc.2024.104436.'
evidence:
- reference: PMID:38977146
reference_title: 'Facing an un-met need in lung cancer screening: The never smokers.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2024 Oct;202:104436. doi: 10.1016/j.critrevonc.2024.104436.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:39008537
title: Complete and durable regression of leptomeningeal involvement during lorlatinib treatment in a patient with lung cancer.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2024 Oct 1;35(9):867-871. doi: 10.1097/CAD.0000000000001637.'
supporting_text: '2024 Oct 1;35(9):867-871. doi: 10.1097/CAD.0000000000001637.'
evidence:
- reference: PMID:39008537
reference_title: Complete and durable regression of leptomeningeal involvement during lorlatinib treatment in a patient with lung cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: '2024 Oct 1;35(9):867-871. doi: 10.1097/CAD.0000000000001637.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:39016057
title: 'Real-world data on ALK rearrangement test in Chinese advanced non-small cell lung cancer (RATICAL): a nationwide multicenter retrospective study.'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Anaplastic lymphoma kinase (ALK) test in advanced non-small cell lung cancer (NSCLC) can help physicians provide target therapies for patients harboring ALK gene rearrangement.
supporting_text: Anaplastic lymphoma kinase (ALK) test in advanced non-small cell lung cancer (NSCLC) can help physicians provide target therapies for patients harboring ALK gene rearrangement.
evidence:
- reference: PMID:39016057
reference_title: 'Real-world data on ALK rearrangement test in Chinese advanced non-small cell lung cancer (RATICAL): a nationwide multicenter retrospective study.'
supports: SUPPORT
evidence_source: OTHER
snippet: Anaplastic lymphoma kinase (ALK) test in advanced non-small cell lung cancer (NSCLC) can help physicians provide target therapies for patients harboring ALK gene rearrangement.
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:39078281
title: SIRT1 silencing promotes EMT and Crizotinib resistance by regulating autophagy through AMPK/mTOR/S6K signaling pathway in EML4-ALK L1196M and EML4-ALK G1202R mutant non-small cell lung cancer cells.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2024 Nov;63(11):2133-2144. doi: 10.1002/mc.23799.'
supporting_text: '2024 Nov;63(11):2133-2144. doi: 10.1002/mc.23799.'
evidence:
- reference: PMID:39078281
reference_title: SIRT1 silencing promotes EMT and Crizotinib resistance by regulating autophagy through AMPK/mTOR/S6K signaling pathway in EML4-ALK L1196M and EML4-ALK G1202R mutant non-small cell lung cancer cells.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2024 Nov;63(11):2133-2144. doi: 10.1002/mc.23799.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:39160676
title: 'Targeting ALK receptors in non-small cell lung cancer: what is the road ahead?'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2024 Aug;28(8):659-668. doi: 10.1080/14728222.2024.2389192.'
supporting_text: '2024 Aug;28(8):659-668. doi: 10.1080/14728222.2024.2389192.'
evidence:
- reference: PMID:39160676
reference_title: 'Targeting ALK receptors in non-small cell lung cancer: what is the road ahead?'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2024 Aug;28(8):659-668. doi: 10.1080/14728222.2024.2389192.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:39231392
title: 'New Benchmark for Targeted Therapies in Lung Cancer: Median Progression-Free Survival for Lorlatinib in Advanced ALK+ Non-Small Cell Lung Cancer Surpasses 5 years.'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2024 Oct 10;42(29):3383-3386. doi: 10.1200/JCO.24.01147.'
supporting_text: '2024 Oct 10;42(29):3383-3386. doi: 10.1200/JCO.24.01147.'
evidence:
- reference: PMID:39231392
reference_title: 'New Benchmark for Targeted Therapies in Lung Cancer: Median Progression-Free Survival for Lorlatinib in Advanced ALK+ Non-Small Cell Lung Cancer Surpasses 5 years.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2024 Oct 10;42(29):3383-3386. doi: 10.1200/JCO.24.01147.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:39392550
title: Taiwan Nationwide Study of First-Line ALK-TKI Therapy in ALK-Positive Lung Adenocarcinoma.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: The clinical outcomes of patients with anaplastic lymphoma kinase-positive (ALK+) advanced lung adenocarcinoma vary according to real-world data.
supporting_text: The clinical outcomes of patients with anaplastic lymphoma kinase-positive (ALK+) advanced lung adenocarcinoma vary according to real-world data.
evidence:
- reference: PMID:39392550
reference_title: Taiwan Nationwide Study of First-Line ALK-TKI Therapy in ALK-Positive Lung Adenocarcinoma.
supports: SUPPORT
evidence_source: OTHER
snippet: The clinical outcomes of patients with anaplastic lymphoma kinase-positive (ALK+) advanced lung adenocarcinoma vary according to real-world data.
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:39465408
title: 'A 16-year evaluation of opportunistic lung cancer screening with low-dose CT in China: comparative findings between non-smokers and smokers.'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: 'A 16-year evaluation of opportunistic lung cancer screening with low-dose CT in China: comparative findings between non-smokers and smokers'
supporting_text: Although low-dose computed tomography (LDCT) screening effectively reduces LC mortality in high-risk individuals with a history of smoking in China, the feasibility and efficacy of lung cancer screening (LCS) in individuals who never smoked versus individuals who smoked remains unclear.
evidence:
- reference: PMID:39465408
reference_title: 'A 16-year evaluation of opportunistic lung cancer screening with low-dose CT in China: comparative findings between non-smokers and smokers.'
supports: SUPPORT
evidence_source: OTHER
snippet: Although low-dose computed tomography (LDCT) screening effectively reduces LC mortality in high-risk individuals with a history of smoking in China, the feasibility and efficacy of lung cancer screening (LCS) in individuals who never smoked versus individuals who smoked remains unclear.
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:39695132
title: Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2024 Dec 18;15(12):912. doi: 10.1038/s41419-024-07272-7.'
supporting_text: '2024 Dec 18;15(12):912. doi: 10.1038/s41419-024-07272-7.'
evidence:
- reference: PMID:39695132
reference_title: Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: '2024 Dec 18;15(12):912. doi: 10.1038/s41419-024-07272-7.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:39904499
title: AXL-Mediated Drug Resistance in ALK-Rearranged NSCLC Enhanced by GAS6 From Macrophages and MMP11 Positive Fibroblasts.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2025 Apr;116(4):1034-1047. doi: 10.1111/cas.70006.'
supporting_text: '2025 Apr;116(4):1034-1047. doi: 10.1111/cas.70006.'
evidence:
- reference: PMID:39904499
reference_title: AXL-Mediated Drug Resistance in ALK-Rearranged NSCLC Enhanced by GAS6 From Macrophages and MMP11 Positive Fibroblasts.
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Apr;116(4):1034-1047. doi: 10.1111/cas.70006.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:39949598
title: Complete response to anti-PD1 therapy and chemotherapy in a patient with ALK-rearranged non-small cell lung cancer.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2025 Jan 15;18(1):37-41. doi: 10.62347/XWHW6190. eCollection 2025.'
supporting_text: '2025 Jan 15;18(1):37-41. doi: 10.62347/XWHW6190. eCollection 2025.'
evidence:
- reference: PMID:39949598
reference_title: Complete response to anti-PD1 therapy and chemotherapy in a patient with ALK-rearranged non-small cell lung cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Jan 15;18(1):37-41. doi: 10.62347/XWHW6190. eCollection 2025.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:40024442
title: 'First-Line Lorlatinib Versus Crizotinib in Asian Patients With Advanced ALK-Positive NSCLC: Five-Year Outcomes From the CROWN Study.'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2025 Jul;20(7):955-968. doi: 10.1016/j.jtho.2025.02.021.'
supporting_text: '2025 Jul;20(7):955-968. doi: 10.1016/j.jtho.2025.02.021.'
evidence:
- reference: PMID:40024442
reference_title: 'First-Line Lorlatinib Versus Crizotinib in Asian Patients With Advanced ALK-Positive NSCLC: Five-Year Outcomes From the CROWN Study.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Jul;20(7):955-968. doi: 10.1016/j.jtho.2025.02.021.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:40190818
title: 'Brief Report: Real-World Treatment Patterns and Clinical Outcomes for Patients With Advanced ALK-Rearranged NSCLC in British Columbia.'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2024 Jun 15;6(4):100697. doi: 10.1016/j.jtocrr.2024.100697. eCollection 2025 Apr.'
supporting_text: '2024 Jun 15;6(4):100697. doi: 10.1016/j.jtocrr.2024.100697. eCollection 2025 Apr.'
evidence:
- reference: PMID:40190818
reference_title: 'Brief Report: Real-World Treatment Patterns and Clinical Outcomes for Patients With Advanced ALK-Rearranged NSCLC in British Columbia.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2024 Jun 15;6(4):100697. doi: 10.1016/j.jtocrr.2024.100697. eCollection 2025 Apr.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:40382267
title: Real-World Creatinine-Based Estimates of Acute and Chronic Kidney Dysfunction in Patients with Advanced ALK-Rearranged Non-Small-Cell Lung Cancer Receiving Tyrosine Kinase Inhibitors.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Anaplastic lymphoma kinase inhibitors (ALKi) are a mainstay of therapy for patients with advanced non-small cell lung cancers (NSCLC).
supporting_text: Anaplastic lymphoma kinase inhibitors (ALKi) are a mainstay of therapy for patients with advanced non-small cell lung cancers (NSCLC).
evidence:
- reference: PMID:40382267
reference_title: Real-World Creatinine-Based Estimates of Acute and Chronic Kidney Dysfunction in Patients with Advanced ALK-Rearranged Non-Small-Cell Lung Cancer Receiving Tyrosine Kinase Inhibitors.
supports: SUPPORT
evidence_source: OTHER
snippet: Anaplastic lymphoma kinase inhibitors (ALKi) are a mainstay of therapy for patients with advanced non-small cell lung cancers (NSCLC).
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:40783309
title: Clinical Outcomes of Patients With Advanced ALK-Rearranged Lung Squamous Cell Carcinoma Treated With ALK Tyrosine Kinase Inhibitors.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: DNA-based next-generation sequencing (NGS) has identified ALK rearrangements in lung squamous cell carcinoma (LUSC), a subset of nonsmall cell lung cancer traditionally lacking effective targeted therapies.
supporting_text: DNA-based next-generation sequencing (NGS) has identified ALK rearrangements in lung squamous cell carcinoma (LUSC), a subset of nonsmall cell lung cancer traditionally lacking effective targeted therapies.
evidence:
- reference: PMID:40783309
reference_title: Clinical Outcomes of Patients With Advanced ALK-Rearranged Lung Squamous Cell Carcinoma Treated With ALK Tyrosine Kinase Inhibitors.
supports: SUPPORT
evidence_source: OTHER
snippet: DNA-based next-generation sequencing (NGS) has identified ALK rearrangements in lung squamous cell carcinoma (LUSC), a subset of nonsmall cell lung cancer traditionally lacking effective targeted therapies.
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:40813394
title: A humanized anaplastic lymphoma kinase (ALK)-directed antibody-drug conjugate with pyrrolobenzodiazepine payload demonstrates efficacy in ALK-expressing cancers.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2025 Aug 15;16(1):7578. doi: 10.1038/s41467-025-62979-1.'
supporting_text: '2025 Aug 15;16(1):7578. doi: 10.1038/s41467-025-62979-1.'
evidence:
- reference: PMID:40813394
reference_title: A humanized anaplastic lymphoma kinase (ALK)-directed antibody-drug conjugate with pyrrolobenzodiazepine payload demonstrates efficacy in ALK-expressing cancers.
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Aug 15;16(1):7578. doi: 10.1038/s41467-025-62979-1.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:41043103
title: 'Real-World Outcomes in Anaplastic Lymphoma Kinase-Positive Advanced Non-Small Cell Lung Cancer in Argentina: A Multicenter Retrospective Study (GAOT-ALK001).'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2025 Oct;11:e2500014. doi: 10.1200/GO-25-00014.'
supporting_text: '2025 Oct;11:e2500014. doi: 10.1200/GO-25-00014.'
evidence:
- reference: PMID:41043103
reference_title: 'Real-World Outcomes in Anaplastic Lymphoma Kinase-Positive Advanced Non-Small Cell Lung Cancer in Argentina: A Multicenter Retrospective Study (GAOT-ALK001).'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2025 Oct;11:e2500014. doi: 10.1200/GO-25-00014.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:41114337
title: 'Patient-derived organoid facilitating personalized medicine in non-small cell lung cancer: two case reports.'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2025 Oct 3;15:1674897. doi: 10.3389/fonc.2025.1674897. eCollection 2025.'
supporting_text: '2025 Oct 3;15:1674897. doi: 10.3389/fonc.2025.1674897. eCollection 2025.'
evidence:
- reference: PMID:41114337
reference_title: 'Patient-derived organoid facilitating personalized medicine in non-small cell lung cancer: two case reports.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Oct 3;15:1674897. doi: 10.3389/fonc.2025.1674897. eCollection 2025.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:41357598
title: 'Managing lorlatinib-induced weight gain through a structured exercise intervention in an ALK+ NSCLC patient: a case report.'
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: In non-small cell lung cancer (NSCLC), ALK tyrosine kinase inhibitors (TKIs) have been associated with significant weight gain, predominantly in fat tissues.
supporting_text: In non-small cell lung cancer (NSCLC), ALK tyrosine kinase inhibitors (TKIs) have been associated with significant weight gain, predominantly in fat tissues.
evidence:
- reference: PMID:41357598
reference_title: 'Managing lorlatinib-induced weight gain through a structured exercise intervention in an ALK+ NSCLC patient: a case report.'
supports: SUPPORT
evidence_source: OTHER
snippet: In non-small cell lung cancer (NSCLC), ALK tyrosine kinase inhibitors (TKIs) have been associated with significant weight gain, predominantly in fat tissues.
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:41424613
title: Integrated Multi-Omics Approaches for Predicting Immune Checkpoint Inhibitor Response in NSCLC - Insights From Genomics, Proteomics, and Metabolomics.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2025 Dec 16;16:167-198. doi: 10.2147/LCTT.S539777. eCollection 2025.'
supporting_text: '2025 Dec 16;16:167-198. doi: 10.2147/LCTT.S539777. eCollection 2025.'
evidence:
- reference: PMID:41424613
reference_title: Integrated Multi-Omics Approaches for Predicting Immune Checkpoint Inhibitor Response in NSCLC - Insights From Genomics, Proteomics, and Metabolomics.
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Dec 16;16:167-198. doi: 10.2147/LCTT.S539777. eCollection 2025.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:41433419
title: Cancer-associated fibroblasts confer ALK inhibitor resistance in EML4-ALK-driven lung cancer by concurrent integrin and MET signaling.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2025 Dec 23;18(918):eads7662. doi: 10.1126/scisignal.ads7662.'
supporting_text: '2025 Dec 23;18(918):eads7662. doi: 10.1126/scisignal.ads7662.'
evidence:
- reference: PMID:41433419
reference_title: Cancer-associated fibroblasts confer ALK inhibitor resistance in EML4-ALK-driven lung cancer by concurrent integrin and MET signaling.
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Dec 23;18(918):eads7662. doi: 10.1126/scisignal.ads7662.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:41591250
title: CT Screening Challenges Amid Rising Threat of Lung Cancer in Individuals Who Have Never Smoked.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2026 Jan;318(1):e251305. doi: 10.1148/radiol.251305.'
supporting_text: '2026 Jan;318(1):e251305. doi: 10.1148/radiol.251305.'
evidence:
- reference: PMID:41591250
reference_title: CT Screening Challenges Amid Rising Threat of Lung Cancer in Individuals Who Have Never Smoked.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2026 Jan;318(1):e251305. doi: 10.1148/radiol.251305.'
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:41816408
title: Outcomes of lung cancer screening by low-dose computed tomography in the health screening program.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Low-dose computed tomography (LDCT) screening reduces lung cancer mortality among high-risk smokers, but data from Southeast Asia remain limited.
supporting_text: Low-dose computed tomography (LDCT) screening reduces lung cancer mortality among high-risk smokers, but data from Southeast Asia remain limited.
evidence:
- reference: PMID:41816408
reference_title: Outcomes of lung cancer screening by low-dose computed tomography in the health screening program.
supports: SUPPORT
evidence_source: OTHER
snippet: Low-dose computed tomography (LDCT) screening reduces lung cancer mortality among high-risk smokers, but data from Southeast Asia remain limited.
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.
- reference: PMID:41959926
title: A meta-analysis of the impact of different ALK variants on targeted therapy efficacy in advanced non-small cell lung cancer.
found_in:
- ALK_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Anaplastic lymphoma kinase (ALK) fusion is an important therapeutic targets in non-small cell lung cancer (NSCLC).
supporting_text: Anaplastic lymphoma kinase (ALK) fusion is an important therapeutic targets in non-small cell lung cancer (NSCLC).
evidence:
- reference: PMID:41959926
reference_title: A meta-analysis of the impact of different ALK variants on targeted therapy efficacy in advanced non-small cell lung cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: Anaplastic lymphoma kinase (ALK) fusion is an important therapeutic targets in non-small cell lung cancer (NSCLC).
explanation: Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

📚

References & Deep Research

References

DOI:10.1177/03008916231202149

Alk-rearranged lung adenocarcinoma: From molecular genetics to therapeutic targeting

1 finding

Anaplastic Lymphoma Kinase (ALK) is a potent oncogenic driver of lung adenocarcinoma (LUAD).

"Anaplastic Lymphoma Kinase (ALK) is a potent oncogenic driver of lung adenocarcinoma (LUAD)."

Show evidence (1 reference)

DOI:10.1177/03008916231202149 SUPPORT Other

"Anaplastic Lymphoma Kinase (ALK) is a potent oncogenic driver of lung adenocarcinoma (LUAD)."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

DOI:10.3389/fimmu.2025.1515748

Non-small cell lung cancer and the tumor microenvironment: making headway from targeted therapies to advanced immunotherapy

1 finding

Non-small cell lung cancer and the tumor microenvironment: making headway from targeted therapies to advanced immunotherapy

"Over the past decades, significant progress has been made in the understanding of non-small cell lung cancer (NSCLC) biology and tumor progression mechanisms, resulting in the development of novel strategies for early detection and wide-ranging care approaches."

Show evidence (1 reference)

DOI:10.3389/fimmu.2025.1515748 SUPPORT Human Clinical

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

DOI:10.3390/biomedicines12020297

Unraveling the Potential of ALK-Targeted Therapies in Non-Small Cell Lung Cancer: Comprehensive Insights and Future Directions

1 finding

and Objective: This review comprehensively explores the intricate landscape of anaplastic lymphoma kinase (ALK), focusing specifically on its pivotal role in non-small cell lung cancer (NSCLC).

"and Objective: This review comprehensively explores the intricate landscape of anaplastic lymphoma kinase (ALK), focusing specifically on its pivotal role in non-small cell lung cancer (NSCLC)."

Show evidence (1 reference)

DOI:10.3390/biomedicines12020297 SUPPORT Human Clinical

"and Objective: This review comprehensively explores the intricate landscape of anaplastic lymphoma kinase (ALK), focusing specifically on its pivotal role in non-small cell lung cancer (NSCLC)."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

DOI:10.3390/ijms26010308

EML4-ALK: Update on ALK Inhibitors

1 finding

EML4-ALK: Update on ALK Inhibitors

"Since the discovery of the first-generation ALK inhibitor, many other tyrosine kinase inhibitors have been demonstrated to be effective in the first line or further lines of treatment in patients with advanced non-small cell lung cancer with EMLA4-ALK translocation."

Show evidence (1 reference)

DOI:10.3390/ijms26010308 SUPPORT Human Clinical

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:22887466

Pemetrexed-based chemotherapy in patients with advanced, ALK-positive non-small cell lung cancer.

No top-level findings curated for this source.

PMID:34147645

Treatment of brain metastases in ALK-positive non-small cell lung cancer.

No top-level findings curated for this source.

PMID:37007097

Association of smoking and ALK tyrosine-kinase inhibitors on overall survival in treatment-naïve ALK-positive advanced lung adenocarcinoma.

No top-level findings curated for this source.

PMID:17625570

Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.

1 finding

2007 Aug 2;448(7153):561-6. doi: 10.1038/nature05945.

"2007 Aug 2;448(7153):561-6. doi: 10.1038/nature05945."

Show evidence (1 reference)

PMID:17625570 SUPPORT Human Clinical

"2007 Aug 2;448(7153):561-6. doi: 10.1038/nature05945."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:20952506

Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene.

1 finding

2010 Dec 1;70(23):9827-36. doi: 10.1158/0008-5472.CAN-10-1671.

"2010 Dec 1;70(23):9827-36. doi: 10.1158/0008-5472.CAN-10-1671."

Show evidence (1 reference)

PMID:20952506 SUPPORT Other

"2010 Dec 1;70(23):9827-36. doi: 10.1158/0008-5472.CAN-10-1671."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:22129856

Clinicopathologic implication of ALK rearrangement in surgically resected lung cancer: a proposal of diagnostic algorithm for ALK-rearranged adenocarcinoma.

1 finding

To characterize the clinicopathologic features of ALK-rearranged lung cancer, and suggest a molecular test protocol for lung adenocarcinoma in the small biopsy specimen.

"To characterize the clinicopathologic features of ALK-rearranged lung cancer, and suggest a molecular test protocol for lung adenocarcinoma in the small biopsy specimen."

Show evidence (1 reference)

PMID:22129856 SUPPORT Human Clinical

"To characterize the clinicopathologic features of ALK-rearranged lung cancer, and suggest a molecular test protocol for lung adenocarcinoma in the small biopsy specimen."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:24199682

Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the tyrosine kinase inhibitor crizotinib in ALK rearranged lung cancer.

1 finding

2014 Jan;83(1):37-43. doi: 10.1016/j.lungcan.2013.09.019.

"2014 Jan;83(1):37-43. doi: 10.1016/j.lungcan.2013.09.019."

Show evidence (1 reference)

PMID:24199682 SUPPORT Other

"2014 Jan;83(1):37-43. doi: 10.1016/j.lungcan.2013.09.019."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:24290361

A novel ALK rearrangement in an inflammatory myofibroblastic tumor in a neonate.

1 finding

2013 Sep-Oct;206(9-10):353-6. doi: 10.1016/j.cancergen.2013.10.002.

"2013 Sep-Oct;206(9-10):353-6. doi: 10.1016/j.cancergen.2013.10.002."

Show evidence (1 reference)

PMID:24290361 SUPPORT Human Clinical

"2013 Sep-Oct;206(9-10):353-6. doi: 10.1016/j.cancergen.2013.10.002."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:24419060

The selective anaplastic lymphoma receptor tyrosine kinase inhibitor ASP3026 induces tumor regression and prolongs survival in non-small cell lung cancer model mice.

1 finding

2014 Feb;13(2):329-40. doi: 10.1158/1535-7163.MCT-13-0395.

"2014 Feb;13(2):329-40. doi: 10.1158/1535-7163.MCT-13-0395."

Show evidence (1 reference)

PMID:24419060 SUPPORT Model Organism

"2014 Feb;13(2):329-40. doi: 10.1158/1535-7163.MCT-13-0395."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:25813151

The clinicopathological significance of ALK rearrangements and KRAS and EGFR mutations in primary pulmonary mucinous adenocarcinoma.

1 finding

2015 Aug;36(8):6417-24. doi: 10.1007/s13277-015-3331-4.

"2015 Aug;36(8):6417-24. doi: 10.1007/s13277-015-3331-4."

Show evidence (1 reference)

PMID:25813151 SUPPORT Human Clinical

"2015 Aug;36(8):6417-24. doi: 10.1007/s13277-015-3331-4."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:26095438

Analysis of Histologic Features Suspecting Anaplastic Lymphoma Kinase (ALK)-Expressing Pulmonary Adenocarcinoma.

1 finding

Analysis of Histologic Features Suspecting Anaplastic Lymphoma Kinase (ALK)-Expressing Pulmonary Adenocarcinoma

"Since 2007 when anaplastic lymphoma kinase (ALK) rearrangements were discovered in non-small cell lung cancer, the ALK gene has received attention due to ALK-targeted therapy, and a notable treatment advantage has been observed in patients harboring the EML4/ALK translocation."

Show evidence (1 reference)

PMID:26095438 SUPPORT Other

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:26536196

Clinical Implications of Variant ALK FISH Rearrangement Patterns.

1 finding

2015 Nov;10(11):1648-52. doi: 10.1097/JTO.0000000000000665.

"2015 Nov;10(11):1648-52. doi: 10.1097/JTO.0000000000000665."

Show evidence (1 reference)

PMID:26536196 SUPPORT Human Clinical

"2015 Nov;10(11):1648-52. doi: 10.1097/JTO.0000000000000665."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:27545757

Clinical Drug-Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib.

1 finding

2017 May;6(3):280-291. doi: 10.1002/cpdd.298.

"2017 May;6(3):280-291. doi: 10.1002/cpdd.298."

Show evidence (1 reference)

PMID:27545757 SUPPORT Human Clinical

"2017 May;6(3):280-291. doi: 10.1002/cpdd.298."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:27604320

Neuronal leucine-rich repeat 1 negatively regulates anaplastic lymphoma kinase in neuroblastoma.

1 finding

2016 Sep 8;6:32682. doi: 10.1038/srep32682.

"2016 Sep 8;6:32682. doi: 10.1038/srep32682."

Show evidence (1 reference)

PMID:27604320 SUPPORT Other

"2016 Sep 8;6:32682. doi: 10.1038/srep32682."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:30008631

Radon Exposure-induced Genetic Variations in Lung Cancers among Never Smokers.

1 finding

Lung cancer in never smokers (LCINS) differs etiologically and clinically from lung cancer attributed to smoking.

"Lung cancer in never smokers (LCINS) differs etiologically and clinically from lung cancer attributed to smoking."

Show evidence (1 reference)

PMID:30008631 SUPPORT Other

"Lung cancer in never smokers (LCINS) differs etiologically and clinically from lung cancer attributed to smoking."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:30255938

Identification of a highly lethal V3(+) TP53(+) subset in ALK(+) lung adenocarcinoma.

1 finding

2019 Jan 1;144(1):190-199. doi: 10.1002/ijc.31893.

"2019 Jan 1;144(1):190-199. doi: 10.1002/ijc.31893."

Show evidence (1 reference)

PMID:30255938 SUPPORT Human Clinical

"2019 Jan 1;144(1):190-199. doi: 10.1002/ijc.31893."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:30599201

Natural History and Factors Associated with Overall Survival in Stage IV ALK-Rearranged Non-Small Cell Lung Cancer.

1 finding

2019 Apr;14(4):691-700. doi: 10.1016/j.jtho.2018.12.014.

"2019 Apr;14(4):691-700. doi: 10.1016/j.jtho.2018.12.014."

Show evidence (1 reference)

PMID:30599201 SUPPORT Other

"2019 Apr;14(4):691-700. doi: 10.1016/j.jtho.2018.12.014."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:30642913

Immunotherapy for the First-Line Treatment of Patients with Metastatic Non-Small Cell Lung Cancer.

1 finding

2019 May 1;25(9):2691-2698. doi: 10.1158/1078-0432.CCR-18-3904.

"2019 May 1;25(9):2691-2698. doi: 10.1158/1078-0432.CCR-18-3904."

Show evidence (1 reference)

PMID:30642913 SUPPORT Human Clinical

"2019 May 1;25(9):2691-2698. doi: 10.1158/1078-0432.CCR-18-3904."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:30902613

Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-Positive Advanced Non-Small Cell Lung Cancer in the Global Phase III ALEX Study.

1 finding

2019 Jul;14(7):1233-1243. doi: 10.1016/j.jtho.2019.03.007.

"2019 Jul;14(7):1233-1243. doi: 10.1016/j.jtho.2019.03.007."

Show evidence (1 reference)

PMID:30902613 SUPPORT Human Clinical

"2019 Jul;14(7):1233-1243. doi: 10.1016/j.jtho.2019.03.007."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:30903971

Lung cancer and residential radon in never-smokers: A pooling study in the Northwest of Spain.

1 finding

Using a pooled case-control study design, including only never-smokers, we have assessed the association of residential radon exposure with the subsequent occurrence of lung cancer.

"Using a pooled case-control study design, including only never-smokers, we have assessed the association of residential radon exposure with the subsequent occurrence of lung cancer."

Show evidence (1 reference)

PMID:30903971 SUPPORT Human Clinical

"Using a pooled case-control study design, including only never-smokers, we have assessed the association of residential radon exposure with the subsequent occurrence of lung cancer."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:30954906

Choosing wisely first line immunotherapy in non-small cell lung cancer (NSCLC): what to add and what to leave out.

1 finding

2019 May;75:39-51. doi: 10.1016/j.ctrv.2019.03.004.

"2019 May;75:39-51. doi: 10.1016/j.ctrv.2019.03.004."

Show evidence (1 reference)

PMID:30954906 SUPPORT Human Clinical

"2019 May;75:39-51. doi: 10.1016/j.ctrv.2019.03.004."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:31010758

[Therapeutic options for oligoprogressive non-small cell lung cancer].

1 finding

2019 Apr;36(4):519-526. doi: 10.1016/j.rmr.2018.04.011.

"2019 Apr;36(4):519-526. doi: 10.1016/j.rmr.2018.04.011."

Show evidence (1 reference)

PMID:31010758 SUPPORT Human Clinical

"2019 Apr;36(4):519-526. doi: 10.1016/j.rmr.2018.04.011."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:31521978

The clinical responses of TNIP2-ALK fusion variants to crizotinib in ALK-rearranged lung adenocarcinoma.

1 finding

2019 Nov;137:19-22. doi: 10.1016/j.lungcan.2019.08.032.

"2019 Nov;137:19-22. doi: 10.1016/j.lungcan.2019.08.032."

Show evidence (1 reference)

PMID:31521978 SUPPORT Human Clinical

"2019 Nov;137:19-22. doi: 10.1016/j.lungcan.2019.08.032."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:31630043

ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib.

1 finding

2019 Dec;138:13-18. doi: 10.1016/j.lungcan.2019.09.023.

"2019 Dec;138:13-18. doi: 10.1016/j.lungcan.2019.09.023."

Show evidence (1 reference)

PMID:31630043 SUPPORT Human Clinical

"2019 Dec;138:13-18. doi: 10.1016/j.lungcan.2019.09.023."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:31633304

Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK-rearranged lung cancer.

1 finding

2019 Dec;11(12):e10581. doi: 10.15252/emmm.201910581.

"2019 Dec;11(12):e10581. doi: 10.15252/emmm.201910581."

Show evidence (1 reference)

PMID:31633304 SUPPORT Other

"2019 Dec;11(12):e10581. doi: 10.15252/emmm.201910581."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:31894386

Unique molecular features and clinical outcomes in young patients with non-small cell lung cancer harboring ALK fusion genes.

1 finding

2020 Apr;146(4):935-944. doi: 10.1007/s00432-019-03116-6.

"2020 Apr;146(4):935-944. doi: 10.1007/s00432-019-03116-6."

Show evidence (1 reference)

PMID:31894386 SUPPORT Other

"2020 Apr;146(4):935-944. doi: 10.1007/s00432-019-03116-6."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:32062313

Lung cancer in never smokers: The role of different risk factors other than tobacco smoking.

1 finding

2020 Apr;148:102895. doi: 10.1016/j.critrevonc.2020.102895.

"2020 Apr;148:102895. doi: 10.1016/j.critrevonc.2020.102895."

Show evidence (1 reference)

PMID:32062313 SUPPORT Other

"2020 Apr;148:102895. doi: 10.1016/j.critrevonc.2020.102895."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:32409712

Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures.

1 finding

2020 May 14;11(1):2393. doi: 10.1038/s41467-020-16212-w.

"2020 May 14;11(1):2393. doi: 10.1038/s41467-020-16212-w."

Show evidence (1 reference)

PMID:32409712 SUPPORT Other

"2020 May 14;11(1):2393. doi: 10.1038/s41467-020-16212-w."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:32482786

Low-dose chest computed tomographic screening and invasive diagnosis of pulmonary nodules for lung cancer in never-smokers.

1 finding

Although lung cancer screening using low-dose computed tomography (LDCT) is now widely used in clinical practice, the characteristics and outcomes of diagnostic procedures related to screen-detected nodules in never-smokers remain unclear.

"Although lung cancer screening using low-dose computed tomography (LDCT) is now widely used in clinical practice, the characteristics and outcomes of diagnostic procedures related to screen-detected nodules in never-smokers remain unclear."

Show evidence (1 reference)

PMID:32482786 SUPPORT Other

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:33222380

Pharmacoenhancement of Low Crizotinib Plasma Concentrations in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer using the CYP3A Inhibitor Cobicistat.

1 finding

2021 Mar;14(2):487-491. doi: 10.1111/cts.12921.

"2021 Mar;14(2):487-491. doi: 10.1111/cts.12921."

Show evidence (1 reference)

PMID:33222380 SUPPORT Other

"2021 Mar;14(2):487-491. doi: 10.1111/cts.12921."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:33655698

Integration of comprehensive genomic profiling, tumor mutational burden, and PD-L1 expression to identify novel biomarkers of immunotherapy in non-small cell lung cancer.

1 finding

2021 Apr;10(7):2216-2231. doi: 10.1002/cam4.3649.

"2021 Apr;10(7):2216-2231. doi: 10.1002/cam4.3649."

Show evidence (1 reference)

PMID:33655698 SUPPORT Other

"2021 Apr;10(7):2216-2231. doi: 10.1002/cam4.3649."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:33761896

EML4-ALK induces cellular senescence in mortal normal human cells and promotes anchorage-independent growth in hTERT-transduced normal human cells.

1 finding

Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC).

"Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC)."

Show evidence (1 reference)

PMID:33761896 SUPPORT Other

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:34271921

Molecular characteristics and clinical outcomes of complex ALK rearrangements identified by next-generation sequencing in non-small cell lung cancers.

1 finding

Complex kinase rearrangement, a mutational process involving one or two chromosomes with clustered rearrangement breakpoints, interferes with the accurate detection of kinase fusions by DNA-based next-generation sequencing (NGS).

"Complex kinase rearrangement, a mutational process involving one or two chromosomes with clustered rearrangement breakpoints, interferes with the accurate detection of kinase fusions by DNA-based next-generation sequencing (NGS)."

Show evidence (1 reference)

PMID:34271921 SUPPORT Other

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:34626839

Deep RNA Sequencing Revealed Fusion Junctional Heterogeneity May Predict Crizotinib Treatment Efficacy in ALK-Rearranged NSCLC.

1 finding

2022 Feb;17(2):264-276. doi: 10.1016/j.jtho.2021.09.016.

"2022 Feb;17(2):264-276. doi: 10.1016/j.jtho.2021.09.016."

Show evidence (1 reference)

PMID:34626839 SUPPORT Human Clinical

"2022 Feb;17(2):264-276. doi: 10.1016/j.jtho.2021.09.016."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:34661367

Phase-separated foci of EML4-ALK facilitate signalling and depend upon an active kinase conformation.

1 finding

2021 Dec 6;22(12):e53693. doi: 10.15252/embr.202153693.

"2021 Dec 6;22(12):e53693. doi: 10.15252/embr.202153693."

Show evidence (1 reference)

PMID:34661367 SUPPORT Other

"2021 Dec 6;22(12):e53693. doi: 10.15252/embr.202153693."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:34994987

Targeted therapy for advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer.

1 finding

Targeted therapies directed at specific driver oncogenes have improved outcomes for individuals with advanced non-small cell lung cancer (NSCLC).

"Targeted therapies directed at specific driver oncogenes have improved outcomes for individuals with advanced non-small cell lung cancer (NSCLC)."

Show evidence (1 reference)

PMID:34994987 SUPPORT Other

"Targeted therapies directed at specific driver oncogenes have improved outcomes for individuals with advanced non-small cell lung cancer (NSCLC)."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:35025076

Psychiatric Adverse Reactions to Anaplastic Lymphoma Kinase Inhibitors in Non-Small-Cell Lung Cancer: Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System.

1 finding

The development of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) has improved the survival outcomes of patients with advanced ALK-rearranged non-small-cell lung cancer (NSCLC).

"The development of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) has improved the survival outcomes of patients with advanced ALK-rearranged non-small-cell lung cancer (NSCLC)."

Show evidence (1 reference)

PMID:35025076 SUPPORT Other

"The development of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) has improved the survival outcomes of patients with advanced ALK-rearranged non-small-cell lung cancer (NSCLC)."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:35085771

EML4-ALK G1202R mutation induces EMT and confers resistance to ceritinib in NSCLC cells via activation of STAT3/Slug signaling.

1 finding

2022 Apr;92:110264. doi: 10.1016/j.cellsig.2022.110264.

"2022 Apr;92:110264. doi: 10.1016/j.cellsig.2022.110264."

Show evidence (1 reference)

PMID:35085771 SUPPORT Other

"2022 Apr;92:110264. doi: 10.1016/j.cellsig.2022.110264."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:35598361

The regulation of CD73 in non-small cell lung cancer.

1 finding

Lung cancer is the leading cause of global cancer-related mortality.

"Lung cancer is the leading cause of global cancer-related mortality."

Show evidence (1 reference)

PMID:35598361 SUPPORT Other

"Lung cancer is the leading cause of global cancer-related mortality."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:35624360

Detecting anaplastic lymphoma kinase (ALK) gene rearrangements with next-generation sequencing remains a reliable approach in patients with non-small-cell lung cancer.

1 finding

2022 Sep;481(3):405-419. doi: 10.1007/s00428-022-03339-y.

"2022 Sep;481(3):405-419. doi: 10.1007/s00428-022-03339-y."

Show evidence (1 reference)

PMID:35624360 SUPPORT Human Clinical

"2022 Sep;481(3):405-419. doi: 10.1007/s00428-022-03339-y."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:36270866

Real-World Treatment Sequencing, Toxicities, Health Utilities, and Survival Outcomes in Patients with Advanced ALK-Rearranged Non-Small-Cell Lung Cancer.

1 finding

2023 Jan;24(1):40-50. doi: 10.1016/j.cllc.2022.09.007.

"2023 Jan;24(1):40-50. doi: 10.1016/j.cllc.2022.09.007."

Show evidence (1 reference)

PMID:36270866 SUPPORT Human Clinical

"2023 Jan;24(1):40-50. doi: 10.1016/j.cllc.2022.09.007."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:37149843

EML4-ALK biology and drug resistance in non-small cell lung cancer: a new phase of discoveries.

1 finding

2023 Jun;17(6):950-963. doi: 10.1002/1878-0261.13446.

"2023 Jun;17(6):950-963. doi: 10.1002/1878-0261.13446."

Show evidence (1 reference)

PMID:37149843 SUPPORT Other

"2023 Jun;17(6):950-963. doi: 10.1002/1878-0261.13446."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:37190044

Gene Fusion Detection in NSCLC Routine Clinical Practice: Targeted-NGS or FISH?

1 finding

2023 Apr 11;12(8):1135. doi: 10.3390/cells12081135.

"2023 Apr 11;12(8):1135. doi: 10.3390/cells12081135."

Show evidence (1 reference)

PMID:37190044 SUPPORT Other

"2023 Apr 11;12(8):1135. doi: 10.3390/cells12081135."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:37597303

Comparative safety of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced anaplastic lymphoma kinase-mutated non-small cell lung cancer: Systematic review and network meta-analysis.

1 finding

2023 Oct;184:107319. doi: 10.1016/j.lungcan.2023.107319.

"2023 Oct;184:107319. doi: 10.1016/j.lungcan.2023.107319."

Show evidence (1 reference)

PMID:37597303 SUPPORT Other

"2023 Oct;184:107319. doi: 10.1016/j.lungcan.2023.107319."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:38042167

Low-dose CT screening among never-smokers with or without a family history of lung cancer in Taiwan: a prospective cohort study.

1 finding

In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis.

"In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis."

Show evidence (1 reference)

PMID:38042167 SUPPORT Other

"In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:38521003

Concurrent inhibition of ALK and SRC kinases disrupts the ALK lung tumor cell proteome.

1 finding

2024 May;74:101081. doi: 10.1016/j.drup.2024.101081.

"2024 May;74:101081. doi: 10.1016/j.drup.2024.101081."

Show evidence (1 reference)

PMID:38521003 SUPPORT Other

"2024 May;74:101081. doi: 10.1016/j.drup.2024.101081."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:38598794

Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer.

1 finding

Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non-small-cell lung cancer (NSCLC).

"Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non-small-cell lung cancer (NSCLC)."

Show evidence (1 reference)

PMID:38598794 SUPPORT Human Clinical

"Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non-small-cell lung cancer (NSCLC)."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:38904987

The Alk receptor tyrosine kinase regulates Sparkly, a novel activity regulating neuropeptide precursor in the Drosophila central nervous system.

1 finding

2024 Jun 21;12:RP88985. doi: 10.7554/eLife.88985.

"2024 Jun 21;12:RP88985. doi: 10.7554/eLife.88985."

Show evidence (1 reference)

PMID:38904987 SUPPORT Other

"2024 Jun 21;12:RP88985. doi: 10.7554/eLife.88985."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:38977146

Facing an un-met need in lung cancer screening: The never smokers.

1 finding

2024 Oct;202:104436. doi: 10.1016/j.critrevonc.2024.104436.

"2024 Oct;202:104436. doi: 10.1016/j.critrevonc.2024.104436."

Show evidence (1 reference)

PMID:38977146 SUPPORT Other

"2024 Oct;202:104436. doi: 10.1016/j.critrevonc.2024.104436."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:39008537

Complete and durable regression of leptomeningeal involvement during lorlatinib treatment in a patient with lung cancer.

1 finding

2024 Oct 1;35(9):867-871. doi: 10.1097/CAD.0000000000001637.

"2024 Oct 1;35(9):867-871. doi: 10.1097/CAD.0000000000001637."

Show evidence (1 reference)

PMID:39008537 SUPPORT Other

"2024 Oct 1;35(9):867-871. doi: 10.1097/CAD.0000000000001637."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:39016057

Real-world data on ALK rearrangement test in Chinese advanced non-small cell lung cancer (RATICAL): a nationwide multicenter retrospective study.

1 finding

Anaplastic lymphoma kinase (ALK) test in advanced non-small cell lung cancer (NSCLC) can help physicians provide target therapies for patients harboring ALK gene rearrangement.

"Anaplastic lymphoma kinase (ALK) test in advanced non-small cell lung cancer (NSCLC) can help physicians provide target therapies for patients harboring ALK gene rearrangement."

Show evidence (1 reference)

PMID:39016057 SUPPORT Other

"Anaplastic lymphoma kinase (ALK) test in advanced non-small cell lung cancer (NSCLC) can help physicians provide target therapies for patients harboring ALK gene rearrangement."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:39078281

SIRT1 silencing promotes EMT and Crizotinib resistance by regulating autophagy through AMPK/mTOR/S6K signaling pathway in EML4-ALK L1196M and EML4-ALK G1202R mutant non-small cell lung cancer cells.

1 finding

2024 Nov;63(11):2133-2144. doi: 10.1002/mc.23799.

"2024 Nov;63(11):2133-2144. doi: 10.1002/mc.23799."

Show evidence (1 reference)

PMID:39078281 SUPPORT Human Clinical

"2024 Nov;63(11):2133-2144. doi: 10.1002/mc.23799."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:39160676

Targeting ALK receptors in non-small cell lung cancer: what is the road ahead?

1 finding

2024 Aug;28(8):659-668. doi: 10.1080/14728222.2024.2389192.

"2024 Aug;28(8):659-668. doi: 10.1080/14728222.2024.2389192."

Show evidence (1 reference)

PMID:39160676 SUPPORT Human Clinical

"2024 Aug;28(8):659-668. doi: 10.1080/14728222.2024.2389192."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:39231392

New Benchmark for Targeted Therapies in Lung Cancer: Median Progression-Free Survival for Lorlatinib in Advanced ALK+ Non-Small Cell Lung Cancer Surpasses 5 years.

1 finding

2024 Oct 10;42(29):3383-3386. doi: 10.1200/JCO.24.01147.

"2024 Oct 10;42(29):3383-3386. doi: 10.1200/JCO.24.01147."

Show evidence (1 reference)

PMID:39231392 SUPPORT Human Clinical

"2024 Oct 10;42(29):3383-3386. doi: 10.1200/JCO.24.01147."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:39392550

Taiwan Nationwide Study of First-Line ALK-TKI Therapy in ALK-Positive Lung Adenocarcinoma.

1 finding

The clinical outcomes of patients with anaplastic lymphoma kinase-positive (ALK+) advanced lung adenocarcinoma vary according to real-world data.

"The clinical outcomes of patients with anaplastic lymphoma kinase-positive (ALK+) advanced lung adenocarcinoma vary according to real-world data."

Show evidence (1 reference)

PMID:39392550 SUPPORT Other

"The clinical outcomes of patients with anaplastic lymphoma kinase-positive (ALK+) advanced lung adenocarcinoma vary according to real-world data."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:39465408

A 16-year evaluation of opportunistic lung cancer screening with low-dose CT in China: comparative findings between non-smokers and smokers.

1 finding

A 16-year evaluation of opportunistic lung cancer screening with low-dose CT in China: comparative findings between non-smokers and smokers

"Although low-dose computed tomography (LDCT) screening effectively reduces LC mortality in high-risk individuals with a history of smoking in China, the feasibility and efficacy of lung cancer screening (LCS) in individuals who never smoked versus individuals who smoked remains unclear."

Show evidence (1 reference)

PMID:39465408 SUPPORT Other

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:39695132

Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer.

1 finding

2024 Dec 18;15(12):912. doi: 10.1038/s41419-024-07272-7.

"2024 Dec 18;15(12):912. doi: 10.1038/s41419-024-07272-7."

Show evidence (1 reference)

PMID:39695132 SUPPORT Other

"2024 Dec 18;15(12):912. doi: 10.1038/s41419-024-07272-7."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:39904499

AXL-Mediated Drug Resistance in ALK-Rearranged NSCLC Enhanced by GAS6 From Macrophages and MMP11 Positive Fibroblasts.

1 finding

2025 Apr;116(4):1034-1047. doi: 10.1111/cas.70006.

"2025 Apr;116(4):1034-1047. doi: 10.1111/cas.70006."

Show evidence (1 reference)

PMID:39904499 SUPPORT Other

"2025 Apr;116(4):1034-1047. doi: 10.1111/cas.70006."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:39949598

Complete response to anti-PD1 therapy and chemotherapy in a patient with ALK-rearranged non-small cell lung cancer.

1 finding

2025 Jan 15;18(1):37-41. doi: 10.62347/XWHW6190. eCollection 2025.

"2025 Jan 15;18(1):37-41. doi: 10.62347/XWHW6190. eCollection 2025."

Show evidence (1 reference)

PMID:39949598 SUPPORT Other

"2025 Jan 15;18(1):37-41. doi: 10.62347/XWHW6190. eCollection 2025."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:40024442

First-Line Lorlatinib Versus Crizotinib in Asian Patients With Advanced ALK-Positive NSCLC: Five-Year Outcomes From the CROWN Study.

1 finding

2025 Jul;20(7):955-968. doi: 10.1016/j.jtho.2025.02.021.

"2025 Jul;20(7):955-968. doi: 10.1016/j.jtho.2025.02.021."

Show evidence (1 reference)

PMID:40024442 SUPPORT Other

"2025 Jul;20(7):955-968. doi: 10.1016/j.jtho.2025.02.021."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:40190818

Brief Report: Real-World Treatment Patterns and Clinical Outcomes for Patients With Advanced ALK-Rearranged NSCLC in British Columbia.

1 finding

2024 Jun 15;6(4):100697. doi: 10.1016/j.jtocrr.2024.100697. eCollection 2025 Apr.

"2024 Jun 15;6(4):100697. doi: 10.1016/j.jtocrr.2024.100697. eCollection 2025 Apr."

Show evidence (1 reference)

PMID:40190818 SUPPORT Other

"2024 Jun 15;6(4):100697. doi: 10.1016/j.jtocrr.2024.100697. eCollection 2025 Apr."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:40382267

Real-World Creatinine-Based Estimates of Acute and Chronic Kidney Dysfunction in Patients with Advanced ALK-Rearranged Non-Small-Cell Lung Cancer Receiving Tyrosine Kinase Inhibitors.

1 finding

Anaplastic lymphoma kinase inhibitors (ALKi) are a mainstay of therapy for patients with advanced non-small cell lung cancers (NSCLC).

"Anaplastic lymphoma kinase inhibitors (ALKi) are a mainstay of therapy for patients with advanced non-small cell lung cancers (NSCLC)."

Show evidence (1 reference)

PMID:40382267 SUPPORT Other

"Anaplastic lymphoma kinase inhibitors (ALKi) are a mainstay of therapy for patients with advanced non-small cell lung cancers (NSCLC)."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:40783309

Clinical Outcomes of Patients With Advanced ALK-Rearranged Lung Squamous Cell Carcinoma Treated With ALK Tyrosine Kinase Inhibitors.

1 finding

DNA-based next-generation sequencing (NGS) has identified ALK rearrangements in lung squamous cell carcinoma (LUSC), a subset of nonsmall cell lung cancer traditionally lacking effective targeted therapies.

"DNA-based next-generation sequencing (NGS) has identified ALK rearrangements in lung squamous cell carcinoma (LUSC), a subset of nonsmall cell lung cancer traditionally lacking effective targeted therapies."

Show evidence (1 reference)

PMID:40783309 SUPPORT Other

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:40813394

A humanized anaplastic lymphoma kinase (ALK)-directed antibody-drug conjugate with pyrrolobenzodiazepine payload demonstrates efficacy in ALK-expressing cancers.

1 finding

2025 Aug 15;16(1):7578. doi: 10.1038/s41467-025-62979-1.

"2025 Aug 15;16(1):7578. doi: 10.1038/s41467-025-62979-1."

Show evidence (1 reference)

PMID:40813394 SUPPORT Other

"2025 Aug 15;16(1):7578. doi: 10.1038/s41467-025-62979-1."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:41043103

Real-World Outcomes in Anaplastic Lymphoma Kinase-Positive Advanced Non-Small Cell Lung Cancer in Argentina: A Multicenter Retrospective Study (GAOT-ALK001).

1 finding

2025 Oct;11:e2500014. doi: 10.1200/GO-25-00014.

"2025 Oct;11:e2500014. doi: 10.1200/GO-25-00014."

Show evidence (1 reference)

PMID:41043103 SUPPORT Human Clinical

"2025 Oct;11:e2500014. doi: 10.1200/GO-25-00014."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:41114337

Patient-derived organoid facilitating personalized medicine in non-small cell lung cancer: two case reports.

1 finding

2025 Oct 3;15:1674897. doi: 10.3389/fonc.2025.1674897. eCollection 2025.

"2025 Oct 3;15:1674897. doi: 10.3389/fonc.2025.1674897. eCollection 2025."

Show evidence (1 reference)

PMID:41114337 SUPPORT Other

"2025 Oct 3;15:1674897. doi: 10.3389/fonc.2025.1674897. eCollection 2025."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:41357598

Managing lorlatinib-induced weight gain through a structured exercise intervention in an ALK+ NSCLC patient: a case report.

1 finding

In non-small cell lung cancer (NSCLC), ALK tyrosine kinase inhibitors (TKIs) have been associated with significant weight gain, predominantly in fat tissues.

"In non-small cell lung cancer (NSCLC), ALK tyrosine kinase inhibitors (TKIs) have been associated with significant weight gain, predominantly in fat tissues."

Show evidence (1 reference)

PMID:41357598 SUPPORT Other

"In non-small cell lung cancer (NSCLC), ALK tyrosine kinase inhibitors (TKIs) have been associated with significant weight gain, predominantly in fat tissues."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:41424613

Integrated Multi-Omics Approaches for Predicting Immune Checkpoint Inhibitor Response in NSCLC - Insights From Genomics, Proteomics, and Metabolomics.

1 finding

2025 Dec 16;16:167-198. doi: 10.2147/LCTT.S539777. eCollection 2025.

"2025 Dec 16;16:167-198. doi: 10.2147/LCTT.S539777. eCollection 2025."

Show evidence (1 reference)

PMID:41424613 SUPPORT Other

"2025 Dec 16;16:167-198. doi: 10.2147/LCTT.S539777. eCollection 2025."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:41433419

Cancer-associated fibroblasts confer ALK inhibitor resistance in EML4-ALK-driven lung cancer by concurrent integrin and MET signaling.

1 finding

2025 Dec 23;18(918):eads7662. doi: 10.1126/scisignal.ads7662.

"2025 Dec 23;18(918):eads7662. doi: 10.1126/scisignal.ads7662."

Show evidence (1 reference)

PMID:41433419 SUPPORT Other

"2025 Dec 23;18(918):eads7662. doi: 10.1126/scisignal.ads7662."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:41591250

CT Screening Challenges Amid Rising Threat of Lung Cancer in Individuals Who Have Never Smoked.

1 finding

2026 Jan;318(1):e251305. doi: 10.1148/radiol.251305.

"2026 Jan;318(1):e251305. doi: 10.1148/radiol.251305."

Show evidence (1 reference)

PMID:41591250 SUPPORT Human Clinical

"2026 Jan;318(1):e251305. doi: 10.1148/radiol.251305."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:41816408

Outcomes of lung cancer screening by low-dose computed tomography in the health screening program.

1 finding

Low-dose computed tomography (LDCT) screening reduces lung cancer mortality among high-risk smokers, but data from Southeast Asia remain limited.

"Low-dose computed tomography (LDCT) screening reduces lung cancer mortality among high-risk smokers, but data from Southeast Asia remain limited."

Show evidence (1 reference)

PMID:41816408 SUPPORT Other

"Low-dose computed tomography (LDCT) screening reduces lung cancer mortality among high-risk smokers, but data from Southeast Asia remain limited."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

PMID:41959926

A meta-analysis of the impact of different ALK variants on targeted therapy efficacy in advanced non-small cell lung cancer.

1 finding

Anaplastic lymphoma kinase (ALK) fusion is an important therapeutic targets in non-small cell lung cancer (NSCLC).

"Anaplastic lymphoma kinase (ALK) fusion is an important therapeutic targets in non-small cell lung cancer (NSCLC)."

Show evidence (1 reference)

PMID:41959926 SUPPORT Other

"Anaplastic lymphoma kinase (ALK) fusion is an important therapeutic targets in non-small cell lung cancer (NSCLC)."

Deep research cited this publication as relevant literature for ALK Rearranged NSCLC.

Deep Research

Disorder ▸

Disorder

Name: ALK-Rearranged Non-Small Cell Lung Cancer
Category:
Existing deep-research providers: falcon
Existing evidence reference count in YAML: 6

Key Pathophysiology Nodes

ALK Gene Rearrangement
Constitutive ALK Signaling
Oncogene Addiction
ALK TKI Resistance
Deep research literature mapping

Citation Inventory (for evidence mapping)

DOI:10.1177/03008916231202149
DOI:10.3389/fimmu.2025.1515748
DOI:10.3390/biomedicines12020297
DOI:10.3390/ijms26010308

Falcon ▸

Disease Pathophysiology Research Report

Edison Scientific Literature 18 citations 2026-01-24T18:51:59.968998

Disease Pathophysiology Research Report

Target Disease - Disease Name: ALK-Rearranged Non-Small Cell Lung Cancer (NSCLC) - MONDO ID: Not retrieved in this evidence set - Category: Thoracic oncology; lung adenocarcinoma subtype driven by ALK gene rearrangements

Plan (concise) 1) Aggregate recent primary reviews and mechanistic studies (emphasis 2023–2024). 2) Extract core pathophysiology, downstream signaling, cellular programs, TME features, co-alterations, resistance mechanisms, and clinical correlates. 3) Compile ontology-grounded annotations. 4) Synthesize progression and phenotype links. 5) Produce tables for ontology mapping and provide fully cited narrative. (testa2024alkrearrangedlungadenocarcinoma pages 1-2, parvaresh2024unravelingthepotential pages 24-27, lucia2025nonsmallcelllung pages 2-3)

Pathophysiology description (narrative) Definition and driver biology ALK-rearranged NSCLC is defined by chromosomal rearrangements that fuse the ALK tyrosine kinase domain to partner genes, most commonly EML4, creating a ligand-independent oncoprotein that constitutively activates receptor tyrosine kinase signaling and drives lung adenocarcinogenesis (approx. 2–8% of LUAD; commonly 2–3%) (Testa et al., Tumori, 2024; DOI:10.1177/03008916231202149; URL: https://doi.org/10.1177/03008916231202149) (testa2024alkrearrangedlungadenocarcinoma pages 1-2). “EML4-ALK arises from different EML4 breakpoints producing main variants—variant 1, variant 2, and variant 3” with variant architecture influencing stability and localization (testa2024alkrearrangedlungadenocarcinoma pages 1-2). Variant biology shapes oncogenic output: all variants retain EML4’s trimerization domain enabling ALK autophosphorylation; V1/V2 have incomplete TAPE domains (HSP90 dependency), whereas V3 is a short variant that co-localizes with microtubules and shows distinct signaling condensates (bioRxiv summary, 2025, variant overview) (jimenez2025unravelingtherapeuticstrategies pages 31-34).

Downstream molecular pathways EML4-ALK engages canonical RTK cascades that mediate proliferation, survival, motility, and adaptive resistance, notably: RAS/RAF/MEK/ERK (MAPK), PI3K/AKT/mTOR, JAK/STAT (especially STAT3), and PLCγ-driven DAG/IP3 signaling; adaptor proteins (e.g., GRB2, SHC, IRS-1) propagate these signals (2024–2025 reviews) (jimenez2025unravelingtherapeuticstrategies pages 28-31, parvaresh2024unravelingthepotential pages 9-11). Preclinical and integrative reviews emphasize that co-inhibition of ALK with MEK or STAT3 can lower survivin, increase BIM, and resensitize resistant cells; ALK post-translational methylation by SMYD2 promotes downstream AKT activation and can be blocked to reduce ALK phosphorylation and tumor growth (Biomedicines, 2024; DOI:10.3390/biomedicines12020297; URL: https://doi.org/10.3390/biomedicines12020297) (parvaresh2024unravelingthepotential pages 13-14, parvaresh2024unravelingthepotential pages 11-13).

Cellular programs affected - Proliferation and survival: constitutive ALK signaling upregulates pro-survival programs via STAT3 (BCL2 family, survivin) and PI3K–AKT, while MAPK promotes mitogenic transcription (parvaresh2024unravelingthepotential pages 11-13, parvaresh2024unravelingthepotential pages 9-11). - EMT, migration, invasion: EMT is linked to specific resistance states; for example, “The EML4‑ALK G1202R on-target mutation induces EMT…increasing migration/invasion via STAT3/Slug,” and MMP9-mediated ALK cleavage can enhance motility via β-catenin nuclear effects (Biomedicines 2024) (parvaresh2024unravelingthepotential pages 13-14, parvaresh2024unravelingthepotential pages 9-11). - Chromatin/transcriptional remodeling and plasticity: YAP/TAZ programs (with AXL/EGFR/TGFBR2 upregulation) and lineage plasticity are implicated in bypass resistance and histologic transformation (jimenez2025unravelingtherapeuticstrategies pages 42-46, parvaresh2024unravelingthepotential pages 13-14).

Tumor microenvironment (TME) and immunobiology ALK+ NSCLC generally exhibits an immunosuppressive TIME with relatively low effective CD8+ T-cell activity and enrichment of suppressive subsets (Tregs and/or M2 macrophages), contributing to poor response to PD-1/PD-L1 blockade; TKI initiation can transiently increase CD8+ T cells, but longer-term treatment fosters immunosuppressive remodeling (Frontiers in Immunology 2025; JITC 2024) (lucia2025nonsmallcelllung pages 2-3, parvaresh2024unravelingthepotential pages 13-14). Clinically relevant correlates include low-to-variable PD-L1 expression and typically low tumor mutational burden (TMB), aligning with reduced ICI efficacy; emphasis is shifting to alternative immunomodulatory approaches (adoptive cells, vaccines) (lucia2025nonsmallcelllung pages 2-3, parvaresh2024unravelingthepotential pages 24-27). Importantly, CNS tropism is frequent at baseline (≈20% present with brain metastases), guiding the use of CNS-penetrant TKIs (jimenez2025unravelingtherapeuticstrategies pages 34-37).

Key molecular players (with ontology references) and co-alterations - Genes/Proteins (HGNC): ALK (driver kinase), EML4 (fusion partner), TP53 (~30% co-altered, associated with inferior TKI outcomes), MET (amplification as bypass), EGFR (ligand-driven activation as bypass), CDKN2A/B (co-deletions), NF2 (loss → mTOR activation), KRAS (copy-number gains/reactivation of MAPK), PTPN11/SHP2 (RAS node dependency), SRC (adaptive resistance), STAT3, MYC, YAP1/WWTR1 (TAZ), AXL, TGFBR2, SMYD2, CDK9, MMP9 (testa2024alkrearrangedlungadenocarcinoma pages 1-2, jimenez2025unravelingtherapeuticstrategies pages 34-37, jimenez2025unravelingtherapeuticstrategies pages 42-46, parvaresh2024unravelingthepotential pages 13-14). - Chemical entities (CHEBI): first-/second-/third-generation ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib) and next-wave inhibitors under development (e.g., 4th-generation concepts NVL‑655, TPX‑0131), and pathway co-inhibitors (EGFR, MEK, PARP) (testa2024alkrearrangedlungadenocarcinoma pages 1-2, parvaresh2024unravelingthepotential pages 24-27, parvaresh2024unravelingthepotential pages 13-14). - Cell types (CL): CD8+ T cells (often functionally constrained), regulatory T cells (Tregs), and M2 macrophages (immunosuppressive) (lucia2025nonsmallcelllung pages 2-3, parvaresh2024unravelingthepotential pages 13-14). - Anatomical locations (UBERON): lung alveolus (primary) and brain parenchyma (frequent metastasis) (testa2024alkrearrangedlungadenocarcinoma pages 1-2, jimenez2025unravelingtherapeuticstrategies pages 34-37).

Embedded ontology mapping table | Category | Item (standardized term) | Ontology | Identifier | Role in disease (1-2 lines) | Key evidence (DOI/URL) | Year | |---|---|---|---:|---|---|---:| | Gene / Protein | ALK | HGNC | HGNC:ALK | Oncogenic fusion kinase driving constitutive RTK signaling (growth/survival). Primary target of ALK-TKIs. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Gene / Protein | EML4 | HGNC | HGNC:EML4 | Fusion partner that provides oligomerization domains; variant structure (V1/V2/V3) alters localization/stability and influences oncogenicity and resistance. | https://doi.org/10.1177/03008916231202149 (testa2024alkrearrangedlungadenocarcinoma pages 1-2), https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Gene / Protein | TP53 | HGNC | HGNC:TP53 | Frequent co-mutation; associated with worse TKI responses and shorter PFS/OS in ALK+ NSCLC. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Gene / Protein | MET | HGNC | HGNC:MET | Bypass driver via amplification/reactivation causing ALK-independent resistance; targetable in combo strategies. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Gene / Protein | EGFR | HGNC | HGNC:EGFR | Can act as bypass pathway (ligand-driven phosphorylation) in ALK-TKI resistance; rationale for combination EGFR+ALK in select cases. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Gene / Protein | CDKN2A | HGNC | HGNC:CDKN2A | Tumor suppressor co-altered in some ALK+ tumors; implicates cell-cycle deregulation and worse prognosis. | https://doi.org/10.1177/03008916231202149 (testa2024alkrearrangedlungadenocarcinoma pages 1-2) | 2024 | | Gene / Protein | CDKN2B | HGNC | HGNC:CDKN2B | Co-deletion with CDKN2A in subsets; contributes to cell-cycle control loss. | https://doi.org/10.1177/03008916231202149 (testa2024alkrearrangedlungadenocarcinoma pages 1-2) | 2024 | | Gene / Protein | NF2 | HGNC | HGNC:NF2 | Loss can activate mTOR signaling and mediate lorlatinib resistance; suggests mTOR-targeted strategies. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Gene / Protein | KRAS | HGNC | HGNC:KRAS | Rare co-alteration; RAS/MAPK reactivation via copy-number gain/reactivation can bypass ALK inhibition. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Gene / Protein | PTPN11 (SHP2) | HGNC | HGNC:PTPN11 | Functional node upstream of RAS—identified as dependency in bypass resistance; combined SHP2+ALK inhibition under evaluation. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Gene / Protein | SRC | HGNC | HGNC:SRC | Src-family kinase implicated in adaptive resistance/tolerance; Src inhibitors show preclinical synergy with ALK-TKIs. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Gene / Protein | STAT3 | HGNC | HGNC:STAT3 | Downstream effector of ALK; mediates survival, EMT and resistance phenotypes (combination ALK+STAT3 can restore sensitivity). | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Gene / Protein | MYC | HGNC | HGNC:MYC | ALK-driven transcriptional programs can upregulate MYC; MYC suppression sensitizes ALK+ cells to TKIs in preclinical data. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Gene / Protein | YAP1 | HGNC | HGNC:YAP1 | YAP-driven transcription links to bypass (AXL/EGFR/TGFBR2) and lineage-plasticity-mediated resistance. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Gene / Protein | WWTR1 (TAZ) | HGNC | HGNC:WWTR1 | Hippo-pathway effector (TAZ) cooperating with YAP in remodeling resistance-associated transcriptional programs. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Gene / Protein | AXL | HGNC | HGNC:AXL | RTK upregulated via YAP/TAZ; contributes to EMT and bypass signaling. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Gene / Protein | TGFBR2 | HGNC | HGNC:TGFBR2 | TGF-β receptor linked to EMT/lineage plasticity and resistance programs. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Gene / Protein | SMYD2 | HGNC | HGNC:SMYD2 | Methyltransferase that post-translationally modifies ALK to promote AKT activation; SMYD2 inhibition synergizes with ALK-TKIs preclinically. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Gene / Protein | CDK9 | HGNC | HGNC:CDK9 | ALK phosphorylation of CDK9 links to homologous recombination and PARP-inhibitor resistance; rationale for ALK+PARP combinations. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Gene / Protein | MMP9 | HGNC | HGNC:MMP9 | Mediates proteolytic ALK cleavage affecting β-catenin release and motility; implicated in invasion/migration. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Biological Process | MAPK cascade (RAS-RAF-MEK-ERK) | GO | GO:MAPK_cascade | Major mitogenic pathway downstream of ALK; reactivation (KRAS, DUSP6 loss) is common bypass route. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Biological Process | PI3K-AKT-mTOR signaling | GO | GO:PI3K-AKT_mTOR | Promotes survival and anti-apoptosis; NF2 loss → mTOR activation mediates lorlatinib resistance. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Biological Process | JAK-STAT cascade | GO | GO:JAK-STAT | STAT3-driven survival and EMT programs downstream of ALK; contributes to resistance and prosurvival gene expression. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Biological Process | Phospholipase C-activating receptor signaling (PLCγ) | GO | GO:PLC_gamma_pathway | ALK activates PLCγ → PKC/Ca2+ signaling affecting proliferation and cytoskeletal dynamics. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Biological Process | Epithelial–mesenchymal transition (EMT) | GO | GO:EMT | EMT is induced by certain ALK mutations (e.g., G1202R) and correlates with invasion and therapeutic resistance. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Biological Process | Cell proliferation | GO | GO:cell_proliferation | Core oncogenic outcome of ALK signaling via MAPK/PI3K pathways. | https://doi.org/10.1177/03008916231202149 (testa2024alkrearrangedlungadenocarcinoma pages 1-2) | 2024 | | Biological Process | Regulation of apoptosis / survival | GO | GO:apoptosis_regulation | ALK signaling upregulates BCL2/survivin and suppresses pro-apoptotic factors; key determinant of TKI response. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Biological Process | Chromatin remodeling / transcriptional reprogramming | GO | GO:chromatin_remodeling | Drives lineage plasticity, immunophenotype changes and SCLC/mesenchymal transformations on therapy pressure. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Biological Process | Cell migration / invasion | GO | GO:cell_migration_invasion | Downstream of EMT, MMP9 activity and cytoskeletal reorganization promoted by ALK fusions. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Biological Process | Immune suppression in TME | GO | GO:immune_suppression_TME | ALK+ tumors often display immunosuppressive TIME (low CD8, high Tregs/M2), limiting ICI responses. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Cellular Component | Plasma membrane | GO | GO:plasma_membrane | Location of RTK signaling complexes and receptor interactions (bypass RTKs). | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Cellular Component | Cytoplasm | GO | GO:cytoplasm | Subcellular compartment for many ALK fusion signaling events and cytosolic adaptor recruitment. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Cellular Component | Microtubules | GO | GO:microtubule | EML4 contribution to microtubule binding (variant-specific localization, e.g., V3) influencing signaling granules. | https://doi.org/10.1177/03008916231202149 (testa2024alkrearrangedlungadenocarcinoma pages 1-2) | 2024 | | Cellular Component | Membraneless cytoplasmic granules | GO | GO:membraneless_granules | Variant-specific condensates concentrate RAS-MAPK components and modulate signaling strength. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Cellular Component | Nucleus | GO | GO:nucleus | Nuclear translocation of transcriptional effectors (β-catenin, MYC) mediates proliferation/invasion programs. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Cell Type | CD8+ T cell | CL | CL:CD8+_T_cell | Key antitumor effector; typically reduced/inactive in ALK+ TIME but can be transiently increased after TKI. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Cell Type | Regulatory T cell (Treg) | CL | CL:Treg | Enriched in ALK+ TIME in some studies, contributing to immunosuppression. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Cell Type | M2 macrophage | CL | CL:M2_macrophage | Immunosuppressive macrophage phenotype associated with ALK+ brain metastases and resistance milieu. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Cell Type | B cell | CL | CL:B_cell | Reduced/variable B cell infiltration reported; role in ALK+ TIME remains under study. | https://doi.org/10.1177/03008916231202149 (testa2024alkrearrangedlungadenocarcinoma pages 1-2) | 2024 | | Anatomical Location | Lung alveolus (primary) | UBERON | UBERON:lung_alveolus | Primary site of tumorigenesis in lung adenocarcinoma harboring ALK fusions. | https://doi.org/10.1177/03008916231202149 (testa2024alkrearrangedlungadenocarcinoma pages 1-2) | 2024 | | Anatomical Location | Brain parenchyma (metastasis) | UBERON | UBERON:brain_parenchyma | ALK+ NSCLC shows CNS tropism; brain metastases common and influence choice of CNS-penetrant TKIs. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Chemical Entity | Lorlatinib | CHEBI | CHEBI:Lorlatinib | Third-generation, CNS-penetrant ALK-TKI active against many single ALK mutations; resistance via compound mutations/bypass emerges. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Chemical Entity | Alectinib | CHEBI | CHEBI:Alectinib | Second-generation ALK inhibitor with superior CNS control vs crizotinib; frontline option. | https://doi.org/10.1177/03008916231202149 (testa2024alkrearrangedlungadenocarcinoma pages 1-2) | 2024 | | Chemical Entity | Brigatinib | CHEBI | CHEBI:Brigatinib | Second-generation ALK-TKI with CNS activity; part of sequencing strategies. | https://doi.org/10.1177/03008916231202149 (testa2024alkrearrangedlungadenocarcinoma pages 1-2) | 2024 | | Chemical Entity | Ceritinib | CHEBI | CHEBI:Ceritinib | Second-generation ALK inhibitor active post-crizotinib; resistance patterns include ALK mutations. | https://doi.org/10.1177/03008916231202149 (testa2024alkrearrangedlungadenocarcinoma pages 1-2) | 2024 | | Chemical Entity | Crizotinib | CHEBI | CHEBI:Crizotinib | First-generation ALK/MET/ROS1 inhibitor; foundational TKI with earlier resistance patterns. | https://doi.org/10.1177/03008916231202149 (testa2024alkrearrangedlungadenocarcinoma pages 1-2) | 2024 | | Chemical Entity | NVL-655 | CHEBI | CHEBI:NVL-655 | Fourth-generation ALK inhibitor in development with activity against lorlatinib-resistant compound mutations (preclinical/early clinical data). | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Chemical Entity | TPX-0131 | CHEBI | CHEBI:TPX-0131 | 4th-gen ALK inhibitor designed to overcome compound mutations; development-stage therapeutic strategy. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Chemical Entity | PARP inhibitors | CHEBI | CHEBI:PARP_inhibitor | Combination rationale with ALK inhibitors due to ALK→CDK9→HR axis; preclinical synergy reported. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Chemical Entity | MEK inhibitors | CHEBI | CHEBI:MEK_inhibitor | Target downstream MAPK reactivation in bypass resistance; ALK+MEK combos show preclinical promise. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 | | Chemical Entity | EGFR inhibitors | CHEBI | CHEBI:EGFR_inhibitor | Employed to target EGFR-driven bypass activation in select ALK-TKI resistant contexts. | https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14) | 2024 |

Table: A compact ontology-mapped table linking genes, processes, compartments, cell types, locations and key drugs to their roles in ALK‑rearranged NSCLC, with evidence citations to recent reviews (2024). This aids database annotation and mechanistic curation.

GO-aligned biological processes and cellular components - Disrupted processes (GO): MAPK cascade; PI3K–AKT–mTOR signaling; JAK–STAT signaling; phospholipase C–activating signaling; epithelial–mesenchymal transition; regulation of apoptosis/survival; chromatin remodeling/transcriptional reprogramming; cell migration/invasion; immune suppression in TME. Evidence: synthesis from 2024–2025 mechanistic reviews indicating ALK→STAT3/ERK/AKT/PLCγ axes, EMT with G1202R, and TME suppression (jimenez2025unravelingtherapeuticstrategies pages 28-31, parvaresh2024unravelingthepotential pages 9-11, parvaresh2024unravelingthepotential pages 13-14, parvaresh2024unravelingthepotential pages 11-13). - Cellular components (GO): plasma membrane (RTK complexes/bypass RTKs), cytoplasm (signalosomes), microtubules (variant V3 localization), membraneless cytoplasmic granules (condensates concentrating RAS-MAPK components), and nucleus (transcriptional effectors) (jimenez2025unravelingtherapeuticstrategies pages 31-34, parvaresh2024unravelingthepotential pages 9-11).

Disease progression: sequence of events 1) Initiation: ALK fusion formation (most commonly EML4‑ALK), generating a constitutively active ALK kinase chimera through EML4-mediated oligomerization and autophosphorylation (testa2024alkrearrangedlungadenocarcinoma pages 1-2, jimenez2025unravelingtherapeuticstrategies pages 31-34). 2) Early tumorigenesis: Oncogene addiction to ALK with activation of MAPK/PI3K/STAT3/PLCγ signaling, promoting proliferation, survival, and invasion programs (jimenez2025unravelingtherapeuticstrategies pages 28-31, parvaresh2024unravelingthepotential pages 11-13). 3) Clinical presentation: Often in younger, light/never-smokers; significant CNS tropism at diagnosis; relative immunologically “cold” TME (jimenez2025unravelingtherapeuticstrategies pages 34-37, lucia2025nonsmallcelllung pages 2-3). 4) Treatment phase: High sensitivity to ALK TKIs; CNS-penetrant agents (alectinib, brigatinib, lorlatinib) improve brain control versus crizotinib (testa2024alkrearrangedlungadenocarcinoma pages 1-2, bearz2025eml4alkupdateon pages 4-6). 5) Acquired resistance evolution: On-target ALK kinase-domain mutations (e.g., L1196M, I1171X, F1174X, G1269A, G1202R), frequently “compound” mutations after lorlatinib; ALK-independent bypass (MET amplification; EGFR/HER signaling; RAS/MAPK reactivation through SHP2, KRAS CN gains, DUSP6 loss; SRC activation); phenotypic plasticity including EMT and histologic transformation (squamous or small-cell) (jimenez2025unravelingtherapeuticstrategies pages 42-46, parvaresh2024unravelingthepotential pages 13-14). 6) Late-stage dynamics: Progressive TME immunosuppression during prolonged TKI exposure; potential opportunities for immunomodulatory strategies beyond PD-1/PD-L1 monotherapy (lucia2025nonsmallcelllung pages 2-3, parvaresh2024unravelingthepotential pages 24-27).

Phenotypic manifestations and clinical correlates - Key clinical phenotypes: Lung adenocarcinoma with high likelihood of brain metastases at baseline and over the disease course; strong initial TKI responses with eventual resistance; generally limited benefit from standalone immune checkpoint blockade (jimenez2025unravelingtherapeuticstrategies pages 34-37, lucia2025nonsmallcelllung pages 2-3). - Variant-specific risk: V3 is frequently associated with more aggressive clinical behavior and enrichment of G1202R upon resistance; V1 more often selects for L1196M/F1174C (2025 synthesis drawing on earlier variant literature) (jimenez2025unravelingtherapeuticstrategies pages 42-46, jimenez2025unravelingtherapeuticstrategies pages 31-34). - PD-L1/TMB: Typically low TMB and variable PD-L1; immunosuppressive TIME features (Tregs, M2 macrophages) likely contribute to modest ICI efficacy (lucia2025nonsmallcelllung pages 2-3, parvaresh2024unravelingthepotential pages 13-14).

Recent developments and latest research (prioritized 2023–2024) - Consolidated fusion/variant biology and clinical implications updated through 2024 Tumori review (Testa et al.), including major EML4‑ALK variants and therapeutic framing (Sep 2024; https://doi.org/10.1177/03008916231202149) (testa2024alkrearrangedlungadenocarcinoma pages 1-2). - Mechanistic advances detailing ALK-driven pathways, EMT linkage to G1202R, ALK methylation by SMYD2→AKT activation, and multi-target combination strategies (ALK+MEK; ALK+STAT3; ALK+EGFR; ALK+PARP) (Biomedicines, Jan 2024; https://doi.org/10.3390/biomedicines12020297) (parvaresh2024unravelingthepotential pages 13-14, parvaresh2024unravelingthepotential pages 11-13). - Resistance in the second-/third-generation era: reviews and syntheses underscore the prevalence of ALK-independent resistance without kinase-domain mutations after earlier TKIs (~50–70% post-crizotinib; ~50% post-2G), with MET, EGFR, YAP/TAZ, SRC, SHP2/RAS reactivation and NF2/mTOR signaling as recurrent routes; after lorlatinib, complex on-target compound mutations and bypass co-emerge (2025 synthesis of 2023–2024 observations) (jimenez2025unravelingtherapeuticstrategies pages 42-46). - Tumor microenvironment dynamics under TKIs: short-term TKI can transiently enhance antitumor immunity (CD8+), whereas long-term therapy fosters an immunosuppressive TME—guiding timing and design of combinations (JITC, Jun 2024; DOI:10.1136/jitc-2024-009165) (lucia2025nonsmallcelllung pages 2-3, parvaresh2024unravelingthepotential pages 13-14). - Brain metastasis management: later-generation TKIs (alectinib, brigatinib, lorlatinib) provide superior CNS control relative to crizotinib and inform frontline selection (IJMS update table, 2025; but CNS emphasis consistent with 2024 landscape) (bearz2025eml4alkupdateon pages 4-6, testa2024alkrearrangedlungadenocarcinoma pages 1-2).

Current applications and implementations - Frontline therapy: alectinib, brigatinib, and lorlatinib as CNS-active first-line options; selection guided by comorbidities, CNS disease, and anticipated resistance patterns (testa2024alkrearrangedlungadenocarcinoma pages 1-2, bearz2025eml4alkupdateon pages 4-6). - Resistance-guided therapy: molecular re-biopsy/ctDNA to define on-target mutations versus bypass mechanisms; lorlatinib for many single mutations; development of 4th‑generation ALK inhibitors (e.g., NVL‑655, TPX‑0131) and rational combinations (ALK+SHP2/MEK/mTOR/EGFR; ALK+PARP) for compound and bypass resistance (parvaresh2024unravelingthepotential pages 24-27, jimenez2025unravelingtherapeuticstrategies pages 42-46, parvaresh2024unravelingthepotential pages 13-14). - Immunotherapy strategies: limited efficacy of PD-1/PD-L1 monotherapy; exploration of ALK vaccines and adoptive cellular strategies to overcome immunosuppression (parvaresh2024unravelingthepotential pages 24-27, lucia2025nonsmallcelllung pages 2-3).

Expert opinions and authoritative analyses - Testa et al. (Tumori 2024) conclude that while “ALK-TKIs have improved outcomes…resistance mechanisms greatly limit durability,” and new strategies aim for long-term remission, underscoring the need for variant-aware and resistance-agnostic approaches (testa2024alkrearrangedlungadenocarcinoma pages 1-2). - Cross-review synthesis highlights that a substantial fraction of progression events are ALK-independent, elevating the importance of bypass-pathway cotargeting (SHP2/RAS-MAPK, MET, EGFR) and vigilance for lineage transformation (jimenez2025unravelingtherapeuticstrategies pages 42-46). - Immunology-focused analyses emphasize immunosuppressive TME characteristics in ALK+ disease and the dynamic remodeling under TKIs, supporting time-sensitive combinations rather than ICI monotherapy (lucia2025nonsmallcelllung pages 2-3, parvaresh2024unravelingthepotential pages 24-27).

Statistics and recent data points - Prevalence: ALK fusions approximately 2–8% of LUAD (often cited 2–3%) (Sep 2024) (testa2024alkrearrangedlungadenocarcinoma pages 1-2). - Variant distribution (ranges vary by cohort): V1 ~33–43%, V3 ~29–42% (2025 synthesis of variant literature; consistent with historical patterns) (jimenez2025unravelingtherapeuticstrategies pages 31-34, jimenez2025unravelingtherapeuticstrategies pages 34-37). - Co-alterations: TP53 is the most frequent (~30% of EML4‑ALK) and is generally associated with worse TKI outcomes (2025 synthesis; 2024 updates) (jimenez2025unravelingtherapeuticstrategies pages 34-37). - Resistance spectra: A large fraction of resistance after crizotinib and second-generation TKIs lacks detectable ALK kinase-domain mutations (~50–70% and ~50%, respectively), indicating prominent bypass resistance; lorlatinib resistance frequently involves compound ALK mutations plus bypass alterations (2025 synthesis summarizing 2023–2024 observations) (jimenez2025unravelingtherapeuticstrategies pages 42-46). - CNS involvement: approximately 20% present with brain metastases at diagnosis (jimenez2025unravelingtherapeuticstrategies pages 34-37).

Evidence items (PMIDs/DOIs/URLs, publication dates) - Testa U, Castelli G, Pelosi E. Alk‑rearranged lung adenocarcinoma: From molecular genetics to therapeutic targeting. Tumori. Sep 2024. DOI:10.1177/03008916231202149. URL: https://doi.org/10.1177/03008916231202149 (testa2024alkrearrangedlungadenocarcinoma pages 1-2). - Parvaresh H, et al. Unraveling the Potential of ALK-Targeted Therapies in NSCLC. Biomedicines. Jan 2024. DOI:10.3390/biomedicines12020297. URL: https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14, parvaresh2024unravelingthepotential pages 11-13, parvaresh2024unravelingthepotential pages 9-11). - De Lucia A, et al. NSCLC and the tumor microenvironment. Frontiers in Immunology. Feb 2025. DOI:10.3389/fimmu.2025.1515748. URL: https://doi.org/10.3389/fimmu.2025.1515748 (lucia2025nonsmallcelllung pages 2-3). - Variant and resistance synthesis (EML4‑ALK V1/V3; on-target vs bypass; SHP2/MAPK/NF2‑mTOR; transformation). 2025 synthesis (bioRxiv-based and review integrations) (jimenez2025unravelingtherapeuticstrategies pages 34-37, jimenez2025unravelingtherapeuticstrategies pages 42-46, jimenez2025unravelingtherapeuticstrategies pages 28-31, jimenez2025unravelingtherapeuticstrategies pages 31-34). - Clinical CNS control and first-line comparisons including post‑crizotinib sequences (summary table). IJMS 2025 update; aligns with 2024 practice trends (bearz2025eml4alkupdateon pages 4-6).

Ontology-grounded annotations - Genes/Proteins (HGNC): ALK (HGNC:ALK); EML4 (HGNC:EML4); TP53 (HGNC:TP53); MET (HGNC:MET); EGFR (HGNC:EGFR); CDKN2A (HGNC:CDKN2A); CDKN2B (HGNC:CDKN2B); NF2 (HGNC:NF2); KRAS (HGNC:KRAS); PTPN11/SHP2 (HGNC:PTPN11); SRC (HGNC:SRC); STAT3 (HGNC:STAT3); MYC (HGNC:MYC); YAP1 (HGNC:YAP1); WWTR1/TAZ (HGNC:WWTR1); AXL (HGNC:AXL); TGFBR2 (HGNC:TGFBR2); SMYD2 (HGNC:SMYD2); CDK9 (HGNC:CDK9); MMP9 (HGNC:MMP9). Roles summarized above (testa2024alkrearrangedlungadenocarcinoma pages 1-2, parvaresh2024unravelingthepotential pages 13-14, jimenez2025unravelingtherapeuticstrategies pages 42-46). - Biological Processes (GO): MAPK cascade; PI3K–AKT–mTOR signaling; JAK–STAT cascade; PLCγ-activating signaling; EMT; proliferation; apoptosis regulation; chromatin remodeling; migration/invasion; immune suppression in TME (jimenez2025unravelingtherapeuticstrategies pages 28-31, parvaresh2024unravelingthepotential pages 9-11, parvaresh2024unravelingthepotential pages 13-14). - Cellular Components (GO): plasma membrane; cytoplasm; microtubules; membraneless cytoplasmic granules; nucleus (jimenez2025unravelingtherapeuticstrategies pages 31-34, parvaresh2024unravelingthepotential pages 9-11). - Cell Types (CL): CD8+ T cell; regulatory T cell; M2 macrophage; B cell (lucia2025nonsmallcelllung pages 2-3, parvaresh2024unravelingthepotential pages 13-14, testa2024alkrearrangedlungadenocarcinoma pages 1-2). - Anatomical Locations (UBERON): lung alveolus; brain parenchyma (testa2024alkrearrangedlungadenocarcinoma pages 1-2, jimenez2025unravelingtherapeuticstrategies pages 34-37). - Chemical Entities (CHEBI): crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, NVL‑655, TPX‑0131, EGFR inhibitors, MEK inhibitors, PARP inhibitors (testa2024alkrearrangedlungadenocarcinoma pages 1-2, parvaresh2024unravelingthepotential pages 24-27, bearz2025eml4alkupdateon pages 4-6, parvaresh2024unravelingthepotential pages 13-14).

Direct supporting quotes - “EML4‑ALK arises from different EML4 breakpoints producing main variants—variant 1 (EML4 exon13::ALK exon20), variant 2 … and variant 3 (EML4 exon6a/6b::ALK exon20)” (Testa 2024) (testa2024alkrearrangedlungadenocarcinoma pages 1-2). - “The EML4‑ALK G1202R on-target mutation induces EMT, increasing migration/invasion via STAT3 and Slug; combined ALK+STAT3 inhibition can restore TKI sensitivity” (Biomedicines 2024) (parvaresh2024unravelingthepotential pages 13-14). - “A large fraction of patients progressing on crizotinib or second-generation inhibitors lack detectable kinase-domain point mutations…indicating widespread ALK-independent resistance” (2025 synthesis summarizing 2023–2024 observations) (jimenez2025unravelingtherapeuticstrategies pages 42-46).

Limitations Some 2025 syntheses are used to summarize 2023–2024 findings where accessible; primary 2024 peer‑reviewed sources (Tumori; Biomedicines) support core mechanisms, while 2025 immunology and mechanistic syntheses are used for TME and resistance contextualization. Where possible, URLs and DOIs are provided.

References (with URLs/dates) mapped to context IDs - Testa U, Castelli G, Pelosi E. Tumori. Sep 2024. https://doi.org/10.1177/03008916231202149 (testa2024alkrearrangedlungadenocarcinoma pages 1-2) - Parvaresh H, et al. Biomedicines. Jan 2024. https://doi.org/10.3390/biomedicines12020297 (parvaresh2024unravelingthepotential pages 13-14, parvaresh2024unravelingthepotential pages 11-13, parvaresh2024unravelingthepotential pages 9-11) - De Lucia A, et al. Frontiers in Immunology. Feb 2025. https://doi.org/10.3389/fimmu.2025.1515748 (lucia2025nonsmallcelllung pages 2-3) - Diaz-Jimenez A. 2025 synthesis: variant distribution; resistance spectrum and bypass pathways including SHP2/RAS-MAPK, MET, EGFR, NF2/mTOR; lineage transformation (jimenez2025unravelingtherapeuticstrategies pages 34-37, jimenez2025unravelingtherapeuticstrategies pages 42-46, jimenez2025unravelingtherapeuticstrategies pages 28-31, jimenez2025unravelingtherapeuticstrategies pages 31-34) - Bearz A, et al. IJMS update table (first-line/CNS control; sequencing context). Jan 2025. https://doi.org/10.3390/ijms26010308 (bearz2025eml4alkupdateon pages 4-6)

Citations for claims in text are provided at the end of the relevant sentences above using context IDs.

References

(testa2024alkrearrangedlungadenocarcinoma pages 1-2): Ugo Testa, Germana Castelli, and Elvira Pelosi. Alk-rearranged lung adenocarcinoma: from molecular genetics to therapeutic targeting. Tumori, 110:88-95, Sep 2024. URL: https://doi.org/10.1177/03008916231202149, doi:10.1177/03008916231202149. This article has 17 citations and is from a peer-reviewed journal.
(parvaresh2024unravelingthepotential pages 24-27): Hannaneh Parvaresh, Ghazaal Roozitalab, Fatemeh Golandam, Payam Behzadi, and Parham Jabbarzadeh Kaboli. Unraveling the potential of alk-targeted therapies in non-small cell lung cancer: comprehensive insights and future directions. Biomedicines, 12:297, Jan 2024. URL: https://doi.org/10.3390/biomedicines12020297, doi:10.3390/biomedicines12020297. This article has 42 citations and is from a poor quality or predatory journal.
(lucia2025nonsmallcelllung pages 2-3): Anna De Lucia, Lucia Mazzotti, Anna Gaimari, Matteo Zurlo, Roberta Maltoni, Claudio Cerchione, Sara Bravaccini, Angelo Delmonte, Lucio Crinò, Patricia Borges de Souza, Luigi Pasini, Fabio Nicolini, Fabrizio Bianchi, Manel Juan, Hugo Calderon, Chiara Magnoni, Luca Gazzola, Paola Ulivi, and Massimiliano Mazza. Non-small cell lung cancer and the tumor microenvironment: making headway from targeted therapies to advanced immunotherapy. Frontiers in Immunology, Feb 2025. URL: https://doi.org/10.3389/fimmu.2025.1515748, doi:10.3389/fimmu.2025.1515748. This article has 10 citations and is from a peer-reviewed journal.
(jimenez2025unravelingtherapeuticstrategies pages 31-34): A Diaz Jimenez. Unraveling therapeutic strategies and tumor suppressor functions in eml4-alk-driven lung tumorigenesis. Unknown journal, 2025.
(jimenez2025unravelingtherapeuticstrategies pages 28-31): A Diaz Jimenez. Unraveling therapeutic strategies and tumor suppressor functions in eml4-alk-driven lung tumorigenesis. Unknown journal, 2025.
(parvaresh2024unravelingthepotential pages 9-11): Hannaneh Parvaresh, Ghazaal Roozitalab, Fatemeh Golandam, Payam Behzadi, and Parham Jabbarzadeh Kaboli. Unraveling the potential of alk-targeted therapies in non-small cell lung cancer: comprehensive insights and future directions. Biomedicines, 12:297, Jan 2024. URL: https://doi.org/10.3390/biomedicines12020297, doi:10.3390/biomedicines12020297. This article has 42 citations and is from a poor quality or predatory journal.
(parvaresh2024unravelingthepotential pages 13-14): Hannaneh Parvaresh, Ghazaal Roozitalab, Fatemeh Golandam, Payam Behzadi, and Parham Jabbarzadeh Kaboli. Unraveling the potential of alk-targeted therapies in non-small cell lung cancer: comprehensive insights and future directions. Biomedicines, 12:297, Jan 2024. URL: https://doi.org/10.3390/biomedicines12020297, doi:10.3390/biomedicines12020297. This article has 42 citations and is from a poor quality or predatory journal.
(parvaresh2024unravelingthepotential pages 11-13): Hannaneh Parvaresh, Ghazaal Roozitalab, Fatemeh Golandam, Payam Behzadi, and Parham Jabbarzadeh Kaboli. Unraveling the potential of alk-targeted therapies in non-small cell lung cancer: comprehensive insights and future directions. Biomedicines, 12:297, Jan 2024. URL: https://doi.org/10.3390/biomedicines12020297, doi:10.3390/biomedicines12020297. This article has 42 citations and is from a poor quality or predatory journal.
(jimenez2025unravelingtherapeuticstrategies pages 42-46): A Diaz Jimenez. Unraveling therapeutic strategies and tumor suppressor functions in eml4-alk-driven lung tumorigenesis. Unknown journal, 2025.
(jimenez2025unravelingtherapeuticstrategies pages 34-37): A Diaz Jimenez. Unraveling therapeutic strategies and tumor suppressor functions in eml4-alk-driven lung tumorigenesis. Unknown journal, 2025.
(bearz2025eml4alkupdateon pages 4-6): Alessandra Bearz, Elisa Bertoli, Brigida Stanzione, Elisa De Carlo, Alessandro Del Conte, Martina Bortolot, Sara Torresan, Eleonora Berto, Valentina Da Ros, Giulia Maria Pelin, Kelly Fassetta, Silvia Rossetto, and Michele Spina. Eml4-alk: update on alk inhibitors. International Journal of Molecular Sciences, 26:308, Jan 2025. URL: https://doi.org/10.3390/ijms26010308, doi:10.3390/ijms26010308. This article has 7 citations and is from a poor quality or predatory journal.

OpenScientist ▸

1. Disease Information

openscientist-autonomous 69 citations 2026-05-06T02:08:06.407062

1. Disease Information

Overview

ALK-rearranged NSCLC is a genomically defined subtype of non-small cell lung cancer characterized by somatic rearrangements of the ALK gene that produce constitutively active fusion proteins, most commonly EML4-ALK. First identified in 2007 by Soda et al., the EML4-ALK fusion gene results from "a small inversion within chromosome 2p [that] results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells" (PMID: 17625570). This landmark discovery established EML4-ALK as a transforming oncogene, as mouse 3T3 fibroblasts expressing the fusion generated transformed foci in culture and subcutaneous tumors in nude mice.

ALK-rearranged NSCLC is recognized as an "oncogene-addicted cancer with peculiar clinical characteristics" (PMID: 39160676), making it exquisitely sensitive to ALK-targeted therapy but largely resistant to immune checkpoint inhibitors.

Key Identifiers

Database	Identifier	Term
NCIT	C215346	ALK-Positive Lung Non-Small Cell Carcinoma
MONDO	0005233	Non-small cell lung carcinoma
MONDO	0005061	Lung adenocarcinoma
SNOMED CT	254637007	Non-small cell lung cancer
ICD-10	C34	Malignant neoplasm of bronchus and lung
MeSH	D002289	Carcinoma, Non-Small-Cell Lung
KEGG	hsa05223	Non-small cell lung cancer pathway
OMIM	164731	ALK gene

Common Synonyms

ALK-positive NSCLC / ALK+ NSCLC
ALK-rearranged lung cancer
EML4-ALK fusion lung cancer
ALK-translocated NSCLC
ALK fusion-positive lung adenocarcinoma

Information Sources

This characterization is derived from aggregated disease-level resources including clinical trial data (CROWN, ALEX, ALINA, ALTA-1L), real-world cohort studies, systematic reviews, and molecular biology research, rather than individual patient EHR data.

2. Etiology

Disease Causal Factors

The primary cause is a somatic chromosomal rearrangement — specifically, a paracentric inversion within chromosome 2p — that fuses the N-terminal portion of EML4 (chr2p21) with the kinase domain of ALK (chr2p23). This creates a constitutively active fusion tyrosine kinase. The rearrangement is exclusively somatic (not inherited) and represents a classic oncogenic driver mutation.

Gene Information: - ALK (Anaplastic Lymphoma Kinase): HGNC:427, Ensembl:ENSG00000171094, UniProt:Q9UM73, NCBI Gene:238, chr2p23.2-p23.1 - EML4 (Echinoderm Microtubule Associated Protein Like 4): HGNC:1316, Ensembl:ENSG00000143924, chr2p21

Risk Factors

Genetic Risk Factors

Somatic EML4-ALK fusion: The defining oncogenic event; detected in 5–7% of adenocarcinomas (PMID: 22129856)
TP53 co-mutations: Present in ~20% of ALK+ cases, associated with dramatically worse outcomes (V3+TP53: HR=9.1 for death, p=0.02) (PMID: 30255938)
EML4-ALK variant type: V3 confers worse prognosis than V1 (HR=1.53, 95%CI: 1.17–1.99, p=0.002) (PMID: 41959926)
Intra-tumoral fusion isoform heterogeneity: 47.1% harbor multiple isoforms; associated with worse PFS (HR=2.45) and OS (HR=3.74) (PMID: 34626839)
No known germline susceptibility loci specifically for ALK rearrangement

Environmental Risk Factors

ALK-rearranged NSCLC predominantly occurs in never-smokers, distinguishing it from smoking-associated NSCLC. Environmental risk factors for lung cancer in never-smokers (LCINS) include:

Radon exposure: OR=1.73 (95%CI: 1.27–2.35) for exposure >=200 Bq/m3 (PMID: 30903971)
Air pollution: Ambient and indoor air pollution
Secondhand smoke: Passive tobacco smoke exposure
Occupational exposures: Various industrial carcinogens
Infectious agents: Mycobacterium tuberculosis and HPV have been implicated (PMID: 32062313)
Cooking fume exposure: Particularly in Asian populations without adequate ventilation

LCINS "constitutes a growing global health challenge, accounting for 10%–25% of lung cancer cases and ranking as the fifth leading cause of cancer-related death worldwide" (PMID: 41591250).

Demographic Enrichment

ALK rearrangement is significantly enriched in: - Adenocarcinomas (6.8%, p<0.001) - Younger patients (p<0.0007) - Women (7.6%, p<0.001) - Never-smokers (8.9%, p<0.001)

(PMID: 22129856)

Protective Factors

No specific genetic protective variants for ALK rearrangement have been identified
General lung cancer risk reduction through radon mitigation, avoidance of secondhand smoke, and cooking ventilation is relevant given the never-smoker predominance

Gene-Environment Interactions

Radon exposure has been linked to genetic alterations in ABL2, SMARCA4, PIK3R2, and MAPK1 in never-smoker lung cancers (PMID: 30008631). Whether these interact specifically with ALK rearrangement susceptibility remains unknown.

3. Phenotypes

Clinical Symptoms and Signs

Phenotype	HPO Term	Type	Frequency	Severity	Progression
Lung neoplasm	HP:0100526	Clinical sign	100%	Variable	Progressive
Cough	HP:0012735	Symptom	50–75%	Mild to severe	Progressive
Dyspnea	HP:0002094	Symptom	30–60%	Moderate to severe	Progressive
Hemoptysis	HP:0002105	Symptom	20–30%	Variable	Episodic
Weight loss	HP:0001824	Symptom	30–50%	Moderate	Progressive
Chest pain	HP:0100749	Symptom	20–40%	Variable	Progressive
Pleural effusion	HP:0002202	Clinical sign	20–35%	Moderate to severe	Progressive
Brain metastases	HP:0100634	Clinical sign	29% at diagnosis	Severe	Progressive
Fatigue	HP:0012378	Symptom	40–60%	Moderate	Progressive

Age of Onset

Typical onset: Adult, median age 55–60 years
Young patients (<50 years): 14.2% of ALK+ cases, median age 44 years (PMID: 31894386)
Onset pattern: Insidious; many patients diagnosed at advanced stage

Distinctive Features

ALK+ NSCLC patients are younger than typical NSCLC: "The median age was 55 years (IQR, 45–67); 86% had Eastern Cooperative Oncology Group <=1, 58% were women, and 57% were nonsmokers. Brain metastases were present at diagnosis in 29%" (PMID: 41043103).

Quality of Life Impact

Brain metastases (cumulative incidence >50%) significantly impair quality of life, causing neurological symptoms, cognitive decline, and functional dependence. ALK TKI treatment substantially improves QoL: the Cochrane analysis demonstrated "ALK inhibitors result in a large increase in the HRQoL measure, time to deterioration (HR 0.52, 95% CI: 0.44 to 0.60)" compared to chemotherapy (PMID: 34994987).

4. Genetic/Molecular Information

Causal Genes

ALK (Anaplastic Lymphoma Kinase) - HGNC: 427 - OMIM: 105590 (gene), 164731 (ALK) - Ensembl: ENSG00000171094 - UniProt: Q9UM73 - Chromosomal location: chr2:29,192,774–29,921,586 (GRCh38) - Normal function: Neuronal receptor tyrosine kinase "essentially and transiently expressed in specific regions of the CNS and PNS, playing important roles in genesis and differentiation of the nervous system" (PMID: 40813394)

EML4 (Echinoderm Microtubule Associated Protein Like 4) - HGNC: 1316 - Ensembl: ENSG00000143924 - Chromosomal location: chr2:42,169,330–42,332,548 (GRCh38)

Pathogenic Variants

Fusion Variants

The EML4-ALK fusion occurs through a paracentric inversion on chromosome 2p with multiple breakpoints in EML4 producing distinct variants:

Variant	EML4 Exon–ALK Exon	Frequency	Clinical Significance
V1 (E13;A20)	Exon 13–Exon 20	~35%	Better prognosis, HSP90-dependent
V2 (E20;A20)	Exon 20–Exon 20	~10%	Intermediate
V3a/b (E6;A20)	Exon 6–Exon 20	~35–45%	Worse prognosis, more resistance

V3 biological basis: "The presence of a partial, probably misfolded beta-propeller domain in variant 1 confers solid-like properties to the compartments it forms, greater dependence on Hsp90 for protein stability and higher cell sensitivity to ALK tyrosine kinase inhibitors (TKIs)" (PMID: 37149843).

Resistance Mutations (Somatic, Acquired)

Mutation	Type	Resistance Pattern
L1196M	Gatekeeper	Crizotinib-resistant
G1202R	Solvent front	Pan-resistant to 1st/2nd gen TKIs
G1269A	ATP-binding	Crizotinib-resistant
I1171T/N/S	Kinase domain	Alectinib-resistant
V1180L	Kinase domain	Alectinib-resistant
L1256F	Kinase domain	Lorlatinib-resistant
Compound mutations	Multiple	Resistant to all single-agent TKIs

Non-EML4 Fusion Partners

Rare ALK fusion partners include KIF5B-ALK, TFG-ALK, TNIP2-ALK (PMID: 31521978), CHRNA7-ALK, TACR1-ALK, HIP1-ALK, DYSF-ALK, ITGAV-ALK (PMID: 31894386), and CSNK1G3-ALK (PMID: 40783309).

Chromosomal Abnormalities

The defining abnormality is inv(2)(p21p23), a small paracentric inversion on chromosome 2p. This is cytogenetically cryptic (not visible on standard karyotype) and requires FISH, IHC, or NGS for detection. Alternative rearrangement patterns include isolated 5' ALK deletion detected by FISH (PMID: 26536196).

Epigenetic Information

Resistance to ALK TKIs involves epigenetic changes including EMT induction via STAT3/Slug pathway (PMID: 35085771), SIRT1 silencing affecting AMPK/mTOR/S6K signaling (PMID: 39078281), and gradual, multifactorial adaptation through "acquisition of multiple cooperating genetic and epigenetic adaptive changes" (PMID: 32409712).

5. Environmental Information

Environmental Factors

Since ALK+ NSCLC predominantly affects never-smokers, relevant environmental factors include: - Residential radon: The most well-established environmental risk factor for LCINS (OR=1.73 for >=200 Bq/m3) (PMID: 30903971) - Air pollution: Particulate matter (PM2.5) exposure - Occupational exposures: Asbestos, heavy metals, organic solvents - Domestic fuel smoke: Coal and biomass combustion

Lifestyle Factors

Smoking: Notably, ALK+ NSCLC is enriched in never-smokers (57–69% across cohorts)
Cooking exposure: Cooking without ventilation assessed in TALENT trial as a risk factor (PMID: 38042167)
Diet and exercise: No specific associations established; exercise intervention shown beneficial for managing lorlatinib-related weight gain (PMID: 41357598)

Infectious Agents

Mycobacterium tuberculosis: History of TB associated with increased LCINS risk (PMID: 32062313)
HPV: Implicated in some LCINS studies, though mechanistic links to ALK rearrangement are unestablished

6. Mechanism / Pathophysiology

Molecular Pathways

The EML4-ALK fusion protein constitutively activates multiple oncogenic signaling cascades:

EML4-ALK Fusion Protein (constitutive kinase)
    |
    +---> RAS-MAPK pathway (hsa04010) -> Cell proliferation
    |       +-- ERK -> Jun -> CD73 upregulation -> Immune evasion
    |
    +---> PI3K-AKT pathway (hsa04151) -> Cell survival, anti-apoptosis
    |       +-- mTOR -> Protein synthesis, cell growth
    |
    +---> JAK-STAT pathway (hsa04630) -> Gene transcription
    |       +-- STAT3 -> EMT, invasion (especially G1202R mutants)
    |
    +---> PLCgamma-ERK pathway -> Proliferative signaling

KEGG Pathways: Non-small cell lung cancer (hsa05223), PI3K-Akt signaling (hsa04151), MAPK signaling (hsa04010), JAK-STAT signaling (hsa04630)

Phase-Separated Signaling Foci

A critical mechanistic insight is that "EML4-ALK V1 and V3 proteins form cytoplasmic foci that contain components of the MAPK, PLCgamma and PI3K signalling pathways" (PMID: 34661367). These phase-separated compartments: - Concentrate signaling components for efficient pathway activation - Are dissolved by ALK inhibitors (ceritinib, lorlatinib) - Show variant-specific behavior: V3 re-localizes to microtubules upon inhibitor treatment - Are stabilized by constitutively active ALK mutations even in the presence of inhibitors

HSP90 Chaperone Dependence

"EML4-ALK [was] identified in complex with multiple cellular chaperones including HSP90" (PMID: 20952506). V1 shows greater HSP90 dependence than V3 due to its misfolded beta-propeller domain, explaining differential drug sensitivity.

Immune Evasion Mechanisms

ALK+ NSCLC exhibits an immune-cold phenotype through multiple mechanisms: - Low TMB: "ALK rearrangements were associated with lower TMB and PD-L1+/TMB-H proportions" (PMID: 33655698) - CD73/adenosine pathway: "Upregulation of CD73/adenosine pathway also contributes to the immune-inert microenvironment" regulated by the ERK-Jun pathway downstream of ALK (PMID: 35598361) - Low CD8+ TILs: Poor T-cell infiltration - Multi-omics confirmation: "ALK/RET/ROS1 fusions [are] linked to immune-cold phenotypes with low tumor mutational burden (TMB) and poor T-cell infiltration" (PMID: 41424613)

GO Terms: protein phosphorylation (GO:0006468), MAPK cascade (GO:0000165), cell proliferation (GO:0008283), signal transduction (GO:0007165), apoptotic process (GO:0006915), cell migration (GO:0016477), epithelial-to-mesenchymal transition (GO:0001837)

Resistance Mechanisms

Resistance evolves through multiple parallel pathways:

Secondary ALK mutations: G1202R (solvent front), L1196M (gatekeeper), compound mutations
Bypass signaling activation:
EGFR activation (PMID: 24199682)
ERBB3/AKT pathway: "Dual inhibition of ALK and ERBB receptors or AKT disrupts RAS/MAPK and AKT/PI3K signalling" (PMID: 39695132)
SRC kinase upregulation (PMID: 38521003)
AXL/GAS6 axis from macrophages and MMP11+ fibroblasts (PMID: 39904499)
YAP activation driving EGFR, AXL, CYR61, and TGFbetaR2 (PMID: 31633304)
Phenotypic transformation: EMT via STAT3/Slug pathway in G1202R mutants — "the expression of EML4-ALK G1202R mutation in A549 cells induced an epithelial-mesenchymal transition (EMT) phenotype and significantly increased the migration and invasion abilities" (PMID: 35085771)
Microenvironment adaptation: Cancer-associated fibroblasts (CAFs) conferring resistance (PMID: 41433419)
Temporal evolution: "Evidence for a hybrid scenario involving the gradual, multifactorial adaptation to the inhibitors through acquisition of multiple cooperating genetic and epigenetic adaptive changes" with temporally restricted collateral sensitivities (PMID: 32409712)

Metabolic Changes

ALK inhibition produces rapid metabolic shutdown: 18F-FDG-PET-CT showed "almost complete inhibition of tumor metabolic activity within 24 hours of ALK inhibitor exposure" (PMID: 20952506).

7. Anatomical Structures Affected

Organ Level

Primary organ: Lung (UBERON:0002048) - Predominantly affects the upper and middle lobes - Adenocarcinoma histology in >95% of cases

Secondary organ involvement (metastatic sites): - Brain (UBERON:0000955) — 29% at diagnosis, cumulative incidence >50% - Liver (UBERON:0002107) — common metastatic site - Bone (UBERON:0002481) — skeletal metastases - Pleura (UBERON:0000977) — pleural effusion in 20–35% - Adrenal glands (UBERON:0002369) - Leptomeninges — up to 10% of ALK+ NSCLC cases

Body systems: Respiratory (primary), nervous (CNS metastases), skeletal, hepatic

Tissue and Cell Level

Epithelial tissue: Lung adenocarcinoma arising from type II pneumocytes or Clara cells
Cell types affected:
Type II alveolar epithelial cells (CL:0002063)
Epithelial cells of lung (CL:0000082)
Bronchial epithelial cells (CL:0002328)

Characteristic Histopathology

ALK+ NSCLC shows distinctive histological features: "Acinar, cribriform, and solid growth patterns, extracellular and intracellular mucin production, and presence of signet-ring-cell element, and psammoma body were significantly more often present in ALK-positive cancer" (PMID: 26095438). Additional features include goblet cell-like cells and nuclear inclusions/grooves resembling papillary thyroid carcinoma.

In primary pulmonary mucinous adenocarcinoma, ALK rearrangements were found in 34.2% and were significantly increased in the solid tumor with mucin production subtype, including signet ring cells, cribriform, and micropapillary patterns (PMID: 25813151).

Subcellular Level

Cytoplasm: Phase-separated EML4-ALK signaling foci (GO:0005737)
Plasma membrane: ALK receptor signaling (GO:0005886)
Microtubules: V3 re-localizes to microtubules upon inhibitor treatment (GO:0015630)
Nucleus: Downstream transcription factor activation (GO:0005634)

8. Temporal Development

Onset

Typical age of onset: Adult; median 55–60 years in most cohorts
Young-onset cases: 14.2% diagnosed before age 50 (median 44 years) (PMID: 31894386)
Onset pattern: Insidious; symptoms develop gradually over weeks to months

Disease Staging (AJCC 8th Edition)

Stage	Description	Treatment Approach
IB–IIIA	Resectable early-stage	Surgery + adjuvant alectinib (ALINA)
IIIB–IIIC	Locally advanced	Multimodal therapy
IV	Metastatic	First-line ALK TKI (lorlatinib/alectinib)

Progression

Natural history without treatment: Rapid progression, median OS ~12 months historically
With ALK TKI therapy: Dramatically prolonged course
Median PFS with lorlatinib: >5 years (not reached at 60 months) (PMID: 39231392)
Median OS with sequential TKIs: 81 months (6.8 years) (PMID: 30599201)
Progression pattern: Typically progressive; oligoprogression amenable to local therapy

Critical Periods

First-line TKI selection: Critical window determining long-term outcomes
Brain metastasis prevention: Early CNS-penetrant TKI (lorlatinib) prevents brain metastases in 96% of patients
Resistance emergence: Temporally restricted collateral sensitivities exist during adaptation, absent in therapy-naive or fully resistant cells

9. Inheritance and Population

Epidemiology

Prevalence of ALK rearrangement in NSCLC: - Overall: 3–7% of NSCLC - "The overall ALK gene rearrangement rate was 6.7% in 23,689 patients with advanced NSCLC and 8.2% in 17,436 patients with advanced lung adenocarcinoma" (PMID: 39016057) - "In a large cohort of 6576 non-small cell lung cancer patients, 343 (5.2%) cases harboring ALK rearrangements were identified" (PMID: 34271921)

Estimated incidence: Given ~2 million new lung cancer cases annually worldwide and ~85% being NSCLC, approximately 50,000–120,000 new ALK+ NSCLC cases occur per year globally.

Genetic Etiology

Inheritance pattern: Not inherited; exclusively somatic
Penetrance: Not applicable (somatic mutation)
Germline mosaicism: Not applicable

Population Demographics

Characteristic	ALK+ NSCLC	General NSCLC
Median age	55–60 years	65–70 years
Female proportion	50–58%	40–45%
Never-smoker	57–69%	10–15%
Adenocarcinoma	>95%	40–50%
Asian ethnicity	Enriched (43.9% in BC Canada cohort)	Variable

Real-world data from multiple geographies confirm these demographics: - Argentina: Median age 55, 58% women, 57% nonsmokers (PMID: 41043103) - Canada: Median age 60, 68.9% never-smokers, 43.9% Asian (PMID: 40190818) - Taiwan: Median age 60, 49.9% female, 67.6% never-smokers (PMID: 39392550)

10. Diagnostics

Clinical Tests

Molecular Testing for ALK Rearrangement

Method	Sensitivity	Utilization	Advantages
IHC (Ventana D5F3)	94–97%	53.6% (China)	Rapid, inexpensive, reliable screen
FISH (break-apart)	Gold standard	15.9%	FDA-approved reference standard
RT-PCR	High	25.4%	Detects known fusion variants
NGS (DNA/RNA)	97%+	18.3%	Comprehensive; detects novel fusions

"IHC-VENTANA-D5F3 was used in 53.6%, real-time polymerase chain reaction (RT-PCR) in 25.4%, next-generation sequencing (NGS) in 18.3%, and fluorescence in-situ hybridization (FISH) in 15.9%" with intra-hospital consistency of 98.2% for IHC (PMID: 39016057).

Important: Discordant ALK IHC+/FISH- cases are "infrequent and associated with a worse outcome" on crizotinib, with PFS at 1 year 58% concordant vs 20% discordant (PMID: 31630043).

RNA-based NGS was confirmed as "the most efficient technique for gene fusion identification in clinical practice, allowing the simultaneous analysis of a large set of genomic rearrangements" (PMID: 37190044).

Imaging

CT chest: Standard for disease staging and response assessment
Brain MRI: Essential at diagnosis (29% brain metastases at presentation)
PET-CT: 18F-FDG PET for staging; shows rapid metabolic response to ALK TKIs
LDCT screening: Detects lung cancer at 0.5–1.2% rate in never-smokers; 78–89% early-stage (PMID: 41816408, PMID: 39465408)

Liquid Biopsy

ctDNA-based NGS: Useful for molecular profiling when tissue unavailable
CSF cfDNA: Superior to plasma for detecting CNS-specific alterations in brain metastases
Concordance: DNA-NGS concordance 97.1% for RNA-NGS, 94.7% for IHC, 97.4% for FISH (PMID: 35624360)

Histopathology

Biopsy findings: Adenocarcinoma with signet ring cells, cribriform/acinar patterns, extracellular mucin, psammoma bodies (PMID: 26095438)
IHC panel: ALK (D5F3), TTF-1, p40, PD-L1

Clinical Criteria

NCCN Guidelines recommend ALK testing for all non-squamous NSCLC and select squamous NSCLC
Testing should be performed at diagnosis before initiating first-line therapy
MAXO terms: molecular testing (MAXO:0000630), immunohistochemistry (MAXO:0000548), fluorescence in situ hybridization (MAXO:0000572)

Differential Diagnosis

ROS1-rearranged NSCLC (similar demographics, different fusion)
EGFR-mutant NSCLC (also in never-smokers but mutually exclusive with ALK)
RET-rearranged NSCLC
KRAS-mutant NSCLC (smoking-associated)
MET exon 14 skipping NSCLC

11. Outcome/Prognosis

Survival and Mortality

Stage IV disease (with ALK TKI therapy):

Metric	Value	Source
Median OS (sequential TKIs)	81 months (6.8 years)	PMID: 30599201
Median OS (real-world)	54.0 months	PMID: 36270866
5-year PFS (lorlatinib, 1L)	63% (Asian)	PMID: 40024442
2-year DFS (adjuvant alectinib)	93.8% (stage II–IIIA)	PMID: 38598794
2-year death rate	21%	PMID: 36270866

"With a median follow-up time of 47 months, the median OS time from diagnosis of stage IV disease was 81 months (6.8 years)" (PMID: 30599201).

Prognostic Factors

Favorable: - EML4-ALK V1 (vs V3) - Wild-type TP53 - Single fusion isoform - Fewer metastatic organs at diagnosis - Treatment with next-generation ALK TKIs (vs crizotinib: HR=3.09 for progression/death) (PMID: 41043103)

Unfavorable: - EML4-ALK V3 (HR=1.53 for PFS vs V1) (PMID: 41959926) - TP53 co-mutation (V3+TP53: HR=9.1 for death) (PMID: 30255938) - Multiple fusion isoforms (HR=3.74 for OS) (PMID: 34626839) - Number of metastatic organs (HR=1.49 per additional organ) (PMID: 30599201) - Crizotinib monotherapy as only TKI

Brain Metastases

Brain metastases present at diagnosis in 29% of patients, with a cumulative incidence exceeding 50%. Lorlatinib provides dramatic CNS control: intracranial ORR 69% vs crizotinib 6% in patients with baseline brain metastases (PMID: 40024442). Complete and durable leptomeningeal regression has been documented with lorlatinib (PMID: 39008537).

12. Treatment

Pharmacotherapy: ALK Tyrosine Kinase Inhibitors

Generation Overview

Generation	Drug	Year Approved	Key Targets	Pivotal Trial
1st	Crizotinib	2011	ALK/ROS1/MET	PROFILE 1014
2nd	Ceritinib	2014	ALK/IGF-1R/InsR	ASCEND-4
2nd	Alectinib	2015	ALK/RET	ALEX, ALINA
2nd	Brigatinib	2017	ALK/ROS1/IGF-1R/FLT3/EGFR	ALTA-1L
2nd	Ensartinib	2020	ALK/ROS1/MET	eXalt3
3rd	Lorlatinib	2018	ALK/ROS1	CROWN

KEGG Drug IDs: Crizotinib (D09731), Alectinib (D10450/D10542), Brigatinib (D10866), Ceritinib (D10551), Ensartinib (D11346/D11356), Lorlatinib (D11012)

Key Efficacy Data

Lorlatinib (CROWN trial, 5-year follow-up): - Median PFS: Not reached (>60 months) - 5-year PFS: 63% (Asian) vs 7% crizotinib (HR=0.22, 95%CI: 0.13–0.37) - Intracranial ORR: 69% vs 6% (brain metastases at baseline) - 96% probability of preventing brain metastases at 5 years (PMID: 40024442)

Alectinib (ALEX trial): - Median PFS: 34.8 months vs crizotinib 10.9 months (HR=0.43) (PMID: 30902613)

Adjuvant alectinib (ALINA trial): - "The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group among patients with stage II or IIIA disease (hazard ratio for disease recurrence or death, 0.24; 95% confidence interval [CI], 0.13 to 0.45; P<0.001)" (PMID: 38598794)

Cochrane meta-analysis of ALK TKIs vs chemotherapy (11 RCTs, 2874 patients): - ALK TKIs vs chemo: PFS HR=0.45 (95%CI: 0.40–0.52, high-certainty evidence) - Next-gen ALK TKIs vs crizotinib: PFS HR=0.39 (95%CI: 0.33–0.46, high-certainty evidence) - ORR in brain metastases: RR=4.88 vs chemo, RR=2.45 vs crizotinib (PMID: 34994987)

Safety Profiles

"The rates of grade 3–4 AEs were: alectinib (16.2%), crizotinib (46.4%), brigatinib (63.7%), ensartinib (75.6%), ceritinib (78.3%), and lorlatinib (91.6%)" (PMID: 37597303). No significant differences were found in fatal AEs or treatment discontinuation rates among the six TKIs.

Drug	Key Toxicities
Crizotinib	GI reactions, visual disorders, neutropenia, edema, hepatotoxicity
Alectinib	Anemia, constipation (best tolerated overall)
Ceritinib	Diarrhea, hepatotoxicity, elevated creatinine
Brigatinib	GI reactions, hypertension, cough, headache
Ensartinib	Skin disorders, pruritus, rash
Lorlatinib	Hyperlipidemia (most frequent), neurocognitive effects (~20%), weight gain

"About 20% of patients receiving lorlatinib experienced cognitive effects and behavioral alterations in pivotal trials" (PMID: 35025076).

Renal effects: AKI occurred in 10% within 90 days of ALK TKI initiation; CKD developed in 14% within 1 year; most cases were mild and did not impact OS (PMID: 40382267).

Weight gain management: Lorlatinib-induced weight gain is manageable with structured exercise intervention including aerobic and resistance training (PMID: 41357598).

Pharmacogenomics

Crizotinib: CYP3A substrate with substantial interindividual PK variability; "patient survival is lower in the quartile with the lowest steady-state trough plasma concentrations" — pharmacoenhancement with cobicistat possible (PMID: 33222380)
Alectinib: CYP3A metabolized to active M4 metabolite; "potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4" — favorable drug interaction profile (PMID: 27545757)
Lorlatinib: CYP3A substrate; strong CYP3A inducers significantly reduce exposure; avoid co-administration

Immunotherapy

ALK+ NSCLC shows limited benefit from immune checkpoint inhibitors due to the immune-cold phenotype. "First-line immunotherapy has limited activity in ALK-rearranged NSCLC; combination of immunotherapy and targeted agents raised safety concerns" (PMID: 30954906). Only 5–15% of metastatic NSCLC patients have EGFR/ALK driver mutations, and these are "largely excluded from immunotherapy trials" (PMID: 30642913). Rare complete responses to anti-PD1 + chemotherapy have been reported in patients with high PD-L1 expression (PMID: 39949598).

Surgical and Interventional

Surgical resection: Standard for early-stage (I–IIIA) disease with adjuvant alectinib
Stereotactic radiosurgery: For oligoprogressive brain metastases
Local ablative therapy: For oligoprogressive disease allowing continuation of systemic TKI (PMID: 31010758)

Experimental Therapies

ALK-directed ADC (CDX0239-PBD): Potent antitumor efficacy in ALK-expressing xenograft models; "ALK RNA, protein, and tumor cell surface expression is elevated in multiple pediatric and adult malignancies with minimal expression in childhood normal tissues" (PMID: 40813394)
Dual ALK + SRC inhibition: "Co-targeting of ALK and SRC showed remarkable inhibitory effects in both ALK-driven murine and ALK-patient-derived lung tumor cells" (PMID: 38521003)
YAP-targeting strategies: Cerivastatin (mevalonate pathway inhibitor) shows activity against ALK TKI resistance in vitro, in vivo, in patient-derived xenografts, and in EML4-ALK transgenic mice (PMID: 31633304)
HSP90 inhibitors: Cause rapid EML4-ALK degradation and transient tumor regression (PMID: 20952506)
ERBB3/AKT dual inhibition: Enhances apoptosis in EML4-ALK+ NSCLC cells (PMID: 39695132)
Clinical trials: NCT04318938 (ABP trial, brigatinib with deep phenotyping), NCT03052608 (CROWN), NCT03456076 (ALINA)

Treatment Strategy

Current recommended algorithm: 1. Molecular testing at diagnosis (IHC screen -> FISH/NGS confirmation) 2. Early-stage (resectable): Surgery + adjuvant alectinib x 24 months 3. Advanced/metastatic: First-line lorlatinib or alectinib 4. Progression: Rebiopsy for resistance mechanism -> targeted 2nd-line 5. Oligoprogression: Local ablative therapy + continue TKI

Sequential TKI treatment: Taiwan nationwide data demonstrated that treatment sequences including next-generation TKIs were independently associated with longer survival: G2 group median TTD 34.3 months vs G1 alone 7.5 months; G2 group OS HR=0.22 (95%CI: 0.15–0.31) vs crizotinib alone (PMID: 39392550).

MAXO terms: chemotherapy (MAXO:0000647), radiation therapy (MAXO:0000014), surgical resection (MAXO:0000448), targeted therapy (MAXO:0001525), molecular testing (MAXO:0000630)

13. Prevention

Primary Prevention

No specific primary prevention exists for ALK rearrangement as it is a stochastic somatic event. General lung cancer risk reduction includes: - Radon mitigation: Home radon testing and mitigation systems - Air pollution reduction: Environmental regulatory measures - Secondhand smoke avoidance: Smoke-free environments - Adequate cooking ventilation: Particularly in Asian populations

Secondary Prevention (Screening)

LDCT screening in never-smokers: - Thailand cohort: LC detection 1.2%, 69.8% stage 0–IB, 85% adenocarcinoma (PMID: 41816408) - China NCC: LC detection 1.0% in never-smokers vs 0.8% in smokers; 78.8% early-stage (PMID: 39465408) - South Korea: LC diagnosed in 0.47% of 17,968 never-smokers (PMID: 32482786)

"Current screening guidelines and eligibility criteria have limited efficacy in identifying LC cases (50%), as most screening programs primarily target subjects with a smoking history" (PMID: 38977146). Expanding LDCT to never-smokers with risk factors (family history, radon exposure) is an important unmet need.

The TALENT trial (Taiwan) specifically screens never-smokers aged 55–75 with risk factors including family history, passive smoke, TB history, and cooking exposure. Among 12,011 participants, lung cancer was diagnosed in 2.6%, with 77.4% at stage I. Family history of lung cancer and age >60 years were independently associated with increased risk (PMID: 38042167).

Tertiary Prevention

Adjuvant ALK TKI therapy: Prevents recurrence after surgery (ALINA trial: 2-year DFS 93.8% vs 63.0% for chemotherapy)
Brain metastasis prevention: CNS-penetrant TKIs (lorlatinib) prevent brain metastases in 96% of patients over 5 years
Resistance monitoring: Serial liquid biopsy for early detection of resistance mutations

14. Other Species / Natural Disease

ALK in Other Species

ALK is evolutionarily conserved and plays roles in nervous system development across species:

Drosophila melanogaster (NCBI Taxon: 7227): ALK ortholog (dAlk) regulates neuropeptide precursors; "The Alk receptor tyrosine kinase regulates Sparkly, a novel activity regulating neuropeptide precursor" (PMID: 38904987)
Mus musculus (NCBI Taxon: 10090): Mouse Alk gene (NCBI Gene: 11682); EML4-ALK transgenic models phenocopy human disease
Danio rerio (zebrafish): ALK ortholog expressed in developing nervous system

ALK in Other Cancer Types

ALK rearrangements/mutations drive multiple cancers across species: - Anaplastic large cell lymphoma (ALCL): NPM1-ALK fusion (KEGG: H01601) - Neuroblastoma: ALK point mutations and amplification (KEGG: H00043); NLRR1 acts as extracellular negative regulator of ALK signaling in neuroblastoma (PMID: 27604320) - Inflammatory myofibroblastic tumors (IMTs): Various ALK fusions, including novel rearrangements in neonates (PMID: 24290361) - Rhabdomyosarcoma: ALK overexpression (PMID: 40813394) - Peripheral T-cell lymphoma (KEGG: H01892)

Comparative Biology

ALK expression is "restricted to the developing nervous system" in normal tissues, with "minimal expression in childhood normal tissues" making it an attractive therapeutic target across species and cancer types (PMID: 40813394). The evolutionary conservation of ALK function from Drosophila to humans supports the use of cross-species models for studying ALK biology.

15. Model Organisms

Genetically Engineered Mouse Models

EML4-ALK transgenic mice: "We generated a genetically engineered mouse model that phenocopies the human disease where this rearranged gene arises" (PMID: 20952506). Key features: - Develops lung adenocarcinoma - Responsive to ALK TKIs (tumor regression with TAE684) - Shows greater tumor regression with ALK inhibitors than carboplatin/paclitaxel - HSP90 inhibitors cause rapid EML4-ALK degradation - Variant-specific models (V1, V3) established showing V3 confers worse ALK inhibitor response (PMID: 38521003)

Xenograft Models

Cell Line	Characteristics	Applications
NCI-H3122	EML4-ALK V1 (E13;A20)	Drug testing, resistance studies
NCI-H2228	EML4-ALK V3 (E6;A20)	Drug testing, intrapleural models
Patient-derived xenografts (PDX)	Variable	Personalized drug testing, resistance

"ASP3026 also showed potent antitumor activities, including tumor shrinkage to a nondetectable level, in hEML4-ALK transgenic mice and prolonged survival in mice with intrapleural NCI-H2228 xenografts" (PMID: 24419060).

YAP targeting was shown effective in both patient-derived xenografts and EML4-ALK transgenic mice for overcoming ALK TKI resistance (PMID: 31633304).

Patient-Derived Models

Patient-derived organoids (PDOs): Used for drug sensitivity testing in refractory ALK+ NSCLC. Case reports demonstrate clinical utility: "PDOs derived from primary and metastatic lesions may help optimize treatment regimens for patients with lung cancer brain metastases, thereby enabling personalized therapy" (PMID: 41114337).

In one case, a patient with complex EML4-ALK fusion variant 3 (E6:A20) and a novel NRXN1-ALK fusion who had progressed on multiple therapies showed PDO sensitivity to brigatinib, which subsequently induced a partial response sustained for 5.8 months.

Cell Line Models

NCI-H3122: Standard V1 model; used extensively for resistance studies including EGFR activation as bypass mechanism (PMID: 24199682)
NCI-H2228: V3 model; used for intrapleural and intrahepatic xenograft studies
EML4-ALK expressing normal human cells: EML4-ALK expression in mortal normal fibroblasts causes cellular senescence; hTERT co-expression enables transformation, providing isogenic model systems (PMID: 33761896)

Model Limitations

Mouse models do not fully recapitulate the immune microenvironment complexity
Xenograft models lack the tumor-stroma interactions of native disease
Species-specific differences in drug metabolism affect pharmacokinetic translation
Brain metastasis models are technically challenging to establish
PDO systems do not capture tumor-immune cell interactions

Key Findings: Detailed Evidence Summary

Finding 1: ALK Prevalence and Demographics

ALK rearrangements occur in 3–7% of NSCLC, predominantly in adenocarcinoma histology. The overall ALK gene rearrangement rate was 6.7% in 23,689 patients with advanced NSCLC (PMID: 39016057). The disease preferentially affects younger (median 55), female (50–58%), never-smoking (57–69%) patients (PMID: 22129856, PMID: 41043103, PMID: 40190818).

Finding 2: Variant-Specific Prognosis

EML4-ALK V3 confers worse prognosis than V1, with meta-analysis showing HR=1.53 (95%CI: 1.17–1.99, p=0.002) for PFS (PMID: 41959926). The combination of V3 + TP53 mutation is particularly lethal (HR=9.1 for death, p=0.02) (PMID: 30255938). The biophysical explanation involves differential phase separation properties and HSP90 dependence between variants (PMID: 37149843).

Finding 3: Dramatic TKI Efficacy

Lorlatinib achieved 5-year PFS of 63% in Asian patients (HR=0.22 vs crizotinib) with 96% brain metastasis prevention (PMID: 40024442). Adjuvant alectinib showed 2-year DFS of 93.8% vs 63.0% for chemotherapy (HR=0.24, P<0.001) (PMID: 38598794). Sequential TKI therapy yields median OS of 81 months (PMID: 30599201).

Finding 4: Multifaceted Resistance

Resistance evolves gradually through multiple cooperating mechanisms (PMID: 32409712) including secondary ALK mutations, bypass signaling (EGFR, SRC, AXL, ERBB3), EMT, YAP activation, and microenvironment adaptation via CAFs.

Finding 5: Immune-Cold Phenotype

Multi-omics studies consistently demonstrate ALK fusions are linked to immune-cold phenotypes with low TMB and poor T-cell infiltration (PMID: 41424613). The CD73/adenosine pathway, regulated by the ALK-ERK-Jun axis, contributes to immune evasion (PMID: 35598361).

Mechanistic Model: Integrated Pathophysiology

INITIATING EVENT
    Somatic inv(2)(p21p23) -> EML4-ALK fusion gene
|
MOLECULAR MECHANISM
    Constitutive ALK kinase activity
|
    +-----------+---------------+
    v           v               v
Phase-separated  HSP90 chaperone  Variant-specific
signaling foci   dependence       properties (V1 vs V3)
    |               |               |
    v               v               v
DOWNSTREAM SIGNALING
    +-- RAS-MAPK -> Proliferation + CD73 -> Immune evasion
    +-- PI3K-AKT-mTOR -> Survival + Growth
    +-- JAK-STAT3 -> Transcription + EMT potential
    +-- PLCgamma-ERK -> Proliferation
|
CELLULAR CONSEQUENCES
    +-- Uncontrolled proliferation
    +-- Anti-apoptotic signaling
    +-- Immune-cold microenvironment (low TMB, CD73/adenosine)
    +-- CNS tropism (brain metastases in >50%)
|
CLINICAL MANIFESTATION
    Lung adenocarcinoma -> Metastases (brain, bone, liver)
|
TREATMENT -> ALK TKI (dissolves signaling foci, blocks kinase)
|
RESISTANCE EVOLUTION (gradual, multifactorial)
    +-- ALK mutations (G1202R, L1196M, compound)
    +-- Bypass signaling (EGFR, SRC, AXL/GAS6, ERBB3)
    +-- Phenotypic: EMT (STAT3/Slug), YAP activation
    +-- Microenvironment: CAF-mediated resistance

Evidence Base: Key Literature

PMID	Year	Key Contribution
17625570	2007	Discovery of EML4-ALK fusion in NSCLC
20952506	2010	EML4-ALK transgenic mouse model; HSP90 dependence
22129856	2012	Demographic enrichment of ALK+ NSCLC
24199682	2014	EGFR activation as crizotinib resistance mechanism
26095438	2015	Histologic features of ALK+ adenocarcinoma
30255938	2018	V3+TP53 lethal subgroup identification
30599201	2019	6.8-year median OS natural history
30902613	2019	ALEX trial: alectinib 34.8-month PFS
31633304	2019	YAP as resistance mechanism and therapeutic target
32409712	2020	Gradual multifactorial resistance evolution
34661367	2021	Phase-separated EML4-ALK signaling foci
34626839	2021	Fusion isoform heterogeneity as prognostic factor
34994987	2021	Cochrane review of ALK TKIs (11 RCTs, 2874 patients)
35598361	2022	CD73/adenosine immune evasion mechanism
37149843	2023	Biophysical basis of V1 vs V3 drug sensitivity
37597303	2023	Network meta-analysis of ALK TKI safety
38598794	2024	ALINA trial: adjuvant alectinib
39016057	2024	Large-scale real-world ALK testing data
40024442	2025	CROWN 5-year data: lorlatinib PFS >60 months
41424613	2025	Multi-omics confirmation of immune-cold phenotype
41959926	2025	Meta-analysis: V3 vs V1 prognosis

Limitations and Knowledge Gaps

No head-to-head trials comparing lorlatinib vs alectinib as first-line therapy; current comparisons rely on matching-adjusted indirect comparisons (MAIC)
Optimal TKI sequencing remains undefined — which TKI should be used first, and what is the best sequence upon progression?
Resistance to lorlatinib: Limited understanding of compound ALK mutations and strategies to overcome them
Immunotherapy role: Optimal approaches to enhance immune response in the immune-cold ALK+ tumor microenvironment remain unclear; CD73/adenosine pathway inhibition is an untested clinical strategy
Screening for never-smokers: No validated risk models for LDCT screening specifically targeting ALK+ NSCLC-prone populations
Long-term outcomes: True 10-year survival data with modern TKI regimens are not yet mature
Mechanisms of CNS tropism: Why ALK+ NSCLC shows preferential brain metastasis remains incompletely understood
Epigenetic contributions: Role of DNA methylation and chromatin remodeling in ALK rearrangement susceptibility and resistance needs further study
Germline susceptibility: Whether certain germline variants predispose to somatic ALK rearrangements is unknown
Health disparities: Access to molecular testing and next-generation ALK TKIs varies dramatically globally

Proposed Follow-up Experiments/Actions

Clinical Priorities

Head-to-head lorlatinib vs alectinib trial: Definitive comparison of the two leading first-line options, particularly for patients without brain metastases
Fourth-generation ALK inhibitors: Development of agents active against compound mutations (G1202R + L1196M, etc.)
CD73/adenosine pathway inhibitors + ALK TKI: Clinical trials combining ALK-targeted therapy with immune microenvironment modulation to overcome intrinsic immunotherapy resistance
Circulating tumor DNA-guided adaptive therapy: Using serial ctDNA monitoring to detect resistance mutations early and guide therapy changes before radiographic progression
LDCT screening trials for never-smokers: Expansion with risk models incorporating family history, radon exposure, and cooking fume exposure; integration with reflex molecular testing of detected nodules

Research Priorities

Single-cell multi-omics of resistance: Characterizing the evolution of TKI resistance at single-cell resolution to identify therapeutic windows and collateral sensitivities
ALK-directed ADCs: Clinical translation of antibody-drug conjugates (e.g., CDX0239-PBD) targeting ALK-expressing tumors
Combination strategies for resistance: SRC+ALK inhibition, ERBB3+ALK inhibition, YAP/mevalonate pathway targeting
Brain metastasis prevention biomarkers: Identifying patients at highest risk for CNS metastases who would benefit most from early CNS-penetrant therapy
Patient-derived organoid platforms: Scaling PDO-guided therapy for personalized treatment selection in refractory disease, particularly for patients with complex or novel fusion variants

Ontology Term Summary

Disease Ontology

MONDO:0005233 (non-small cell lung carcinoma)
MONDO:0005061 (lung adenocarcinoma)
NCIT:C215346 (ALK-Positive Lung Non-Small Cell Carcinoma)

Phenotype Ontology (HPO)

HP:0100526 (Neoplasm of the lung)
HP:0012735 (Cough)
HP:0002094 (Dyspnea)
HP:0002105 (Hemoptysis)
HP:0001824 (Weight loss)
HP:0100749 (Chest pain)
HP:0002202 (Pleural effusion)
HP:0100634 (Brain metastases)
HP:0012378 (Fatigue)

Gene Ontology (Biological Process)

GO:0006468 (protein phosphorylation)
GO:0000165 (MAPK cascade)
GO:0008283 (cell proliferation)
GO:0007165 (signal transduction)
GO:0006915 (apoptotic process)
GO:0016477 (cell migration)
GO:0001837 (epithelial to mesenchymal transition)

Gene Ontology (Cellular Component)

GO:0005737 (cytoplasm)
GO:0005886 (plasma membrane)
GO:0015630 (microtubule cytoskeleton)
GO:0005634 (nucleus)

Cell Ontology (CL)

CL:0002063 (type II pneumocyte)
CL:0000082 (epithelial cell of lung)
CL:0002328 (bronchial epithelial cell)

Anatomy Ontology (UBERON)

UBERON:0002048 (lung)
UBERON:0002185 (bronchus)
UBERON:0000955 (brain)
UBERON:0000977 (pleura)
UBERON:0002107 (liver)
UBERON:0002481 (bone tissue)
UBERON:0002369 (adrenal gland)

Chemical Entities (CHEBI)

Crizotinib (KEGG: D09731)
Alectinib (KEGG: D10450)
Lorlatinib (KEGG: D11012)
Brigatinib (KEGG: D10866)
Ceritinib (KEGG: D10551)
Ensartinib (KEGG: D11346)

Medical Action Ontology (MAXO)

MAXO:0000647 (chemotherapy)
MAXO:0000014 (radiation therapy)
MAXO:0000448 (surgical resection)
MAXO:0001525 (targeted therapy)
MAXO:0000630 (molecular testing)
MAXO:0000548 (immunohistochemistry)
MAXO:0000572 (fluorescence in situ hybridization)

Report generated from systematic analysis of 129 papers, 22 confirmed findings, across 5 investigation iterations. All citations verified against original abstracts. Last updated: 2026-05-06.

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Classifications

Subtypes

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Treatments

Biochemical Markers

Computational Models

Source YAML

References & Deep Research

References

Deep Research

Disorder

Key Pathophysiology Nodes

Citation Inventory (for evidence mapping)

1. Disease Information

Overview

Key Identifiers

Common Synonyms

Information Sources

2. Etiology

Disease Causal Factors

Risk Factors

Genetic Risk Factors

Environmental Risk Factors

Demographic Enrichment

Protective Factors

Gene-Environment Interactions

3. Phenotypes

Clinical Symptoms and Signs

Age of Onset

Distinctive Features

Quality of Life Impact

4. Genetic/Molecular Information

Causal Genes

Pathogenic Variants

Fusion Variants

Resistance Mutations (Somatic, Acquired)

Non-EML4 Fusion Partners

Chromosomal Abnormalities

Epigenetic Information

5. Environmental Information

Environmental Factors

Lifestyle Factors

Infectious Agents

6. Mechanism / Pathophysiology

Molecular Pathways

Phase-Separated Signaling Foci

HSP90 Chaperone Dependence

Immune Evasion Mechanisms

Resistance Mechanisms

Metabolic Changes

7. Anatomical Structures Affected

Organ Level

Tissue and Cell Level

Characteristic Histopathology

Subcellular Level

8. Temporal Development

Onset

Disease Staging (AJCC 8th Edition)

Progression

Critical Periods

9. Inheritance and Population

Epidemiology

Genetic Etiology

Population Demographics

10. Diagnostics

Clinical Tests

Molecular Testing for ALK Rearrangement

Imaging

Liquid Biopsy

Histopathology

Clinical Criteria

Differential Diagnosis

11. Outcome/Prognosis

Survival and Mortality