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ALK is a gene fusion driver in about 4 to 5% of non-small-cell lung cancers that responds to a succession of ALK inhibitor pills. Lorlatinib kept about 60% of patients progression-free at five years, alectinib is approved after surgery, and neladalkib targets compound resistance mutations.
ALK rearrangements occur in ~4-5% of NSCLC, typically in younger never-smokers. Lorlatinib achieved 5-year PFS of ~60% in CROWN, the longest of any targeted therapy in metastatic NSCLC. Alectinib is approved in the adjuvant setting (ALINA). Fourth-generation inhibitors (neladalkib) address compound resistance mutations.
In plain words · ALK is a gene fusion driver in about 4 to 5% of non-small-cell lung cancers that responds to a succession of ALK inhibitor pills. Lorlatinib kept about 60% of patients progression-free at five years, alectinib is approved after surgery, and neladalkib targets compound resistance mutations.
Backbone ribbon from PDB 3AOX. RCSB PDB 3AOX. The ribbon widens where the chain is folded into a regular pattern and narrows where it is a loose loop.
Backbone ribbon with the bound drug in ball-and-stick (pink carbons). The wireframe view adds the pocket residues within 5 Å as a thin cage.
ALK is a gene fusion driver in about 4 to 5% of non-small-cell lung cancers that responds to a succession of ALK inhibitor pills. Lorlatinib kept about 60% of patients progression-free at five years, alectinib is approved after surgery, and neladalkib targets compound resistance mutations.
ALK is a receptor tyrosine kinase; the EML4-ALK fusion is most common. It is also altered in anaplastic large-cell lymphoma and neuroblastoma.
11 products aim at ALK: small molecules, degraders and other agents. Kinases are switched on by binding ATP inside the cell, so most drugs are small molecules shaped to plug that ATP pocket.
Tumour-specific alteration: 1 of 1 label readouts filed under it measure a sequence variant (ALK fusion (ALK-positive)) absent from normal cells. HPA ALK: RNA tissue enhanced (brain 2 nTPM, pituitary gland 2 nTPM, testis 2 nTPM); high antibody staining in 3 normal tissues; highest cancer staining skin cancer (4 of 10 high). Distribution: 2 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Lung cancer (all types), Childhood cancers (all types)); approvals of single-target medicines aimed at it also list Brain and spinal cord tumours (all types), not counted; Open Targets associates it with 5 specific cancer types at or above 0.5 (neuroblastoma, neuroblastoma, susceptibility to, 3, non-small cell lung carcinoma, lung cancer, anaplastic large cell lymphoma). (Rule 3 of scripts/fetch-target-specificity.ts.)
Sources: ALK fusion (ALK-positive) label threshold; Human Protein Atlas ALK tissue; Open Targets ENSG00000171094 associations
First described 1994. Earliest sequence paper UniProt cites for the protein: Morris S.W. et al, Science, 1994, "Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma". Source.
What a pathology or genomic report can say about this target, each with the thresholds approvals use.
Cell lines and mouse models for this target →
ALK is a receptor tyrosine kinase; the EML4-ALK fusion is most common. It is also altered in anaplastic large-cell lymphoma and neuroblastoma.
RNA: tissue enhanced (brain 2 nTPM, pituitary gland 2 nTPM, testis 2 nTPM), detected in some normal tissues.
Medium: Caudate, Skin.
RNA group enriched: Glioblastoma Multiforme 2 pTPM, Ovary Serous Cystadenocarcinoma 1 pTPM, Skin Cutaneous Melanoma 3 pTPM, Thyroid Carcinoma 2 pTPM.
Medium only: endometrial cancer, melanoma, ovarian cancer, urothelial cancer.
HPA ALK tissue · HPA ALK pathology · HPA protein class: CD markers, FDA approved drug targets
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Neuroblastoma | 8-14% | Activating mutation/amplification | Higher at relapse | Wikipedia |
| Non-small-cell lung cancer | 3-6% | Rearrangement, usually EML4-ALK | cBioPortal structural variants: 109 of 2,422, 4.5%, in luad_mskcc_2023_met_organotropism (EML4 the partner in 94 of the events); 31 of 915, 3.4%, in lung_msk_2017; 75 of 2,621, 2.9%, in nsclc_ctdx_msk_2022; 13 of 232, 5.6%, in lung_nci_2022; 6 of 181, 3.3%, in luad_oncosg_2020. The original description found the fusion in 5 of 75 patients, 6.7% (Soda 2007), and the Lung Cancer Mutation Consortium found ALK rearrangement in 57 of 733, 8%, by fluorescence in situ hybridisation (Kris 2014). | cBioPortal (TCGA) |
| Non-small-cell lung cancer | 3-5% | Rearrangement | Younger never-smokers | cBioPortal (TCGA) |
| Pancreatic ductal adenocarcinoma | 0.2% | Gene fusion (EML4-ALK, STRN-ALK) | 5 of 3,170 profiled cancers, 0.16%, all KRAS wild-type and all under 50, where ALK fusions were 1.3% of tumours in patients under 50; 3 of 4 treated with an ALK inhibitor had stable disease, radiographic response or CA 19-9 normalisation (Singhi 2017); 1 of 2,336 (ASAP2-ALK) in pdac_msk_2024 (cBioPortal); 2.6% of 266 KRAS wild-type tumours (Philip 2022). | doi.org |
| Colorectal cancer | 0.1% | Gene fusion | cBioPortal structural variants: 9 of 7,237, 0.12%, in crc_msk_2026; 1 of 594 (PPP4R3B-ALK) in coadread_tcga_pan_can_atlas_2018. ALK point mutations read 388 of 7,237 in crc_msk_2026 but are overwhelmingly passengers in hypermutated tumours, not the fusions that matter. | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Alectinib is a well-tolerated ALK pill, standard first line for years and, since 2024, the first targeted therapy given after surgery for ALK-positive lung cancer.
Brigatinib is an ALK pill with strong brain activity, approved first after crizotinib and then first line after beating it in ALTA-1L.
Ceritinib is a second-generation ALK pill for lung cancer, effective after crizotinib but with gastrointestinal toxicity that limited uptake.
Crizotinib was the first ALK inhibitor, approved four years after ALK fusions were found in lung cancer; it was also the first drug for ROS1 lung cancer and for ALK-positive lymphoma and inflammatory myofibroblastic tumour in children.
A Chinese-developed ALK pill approved in the US in December 2024 for first-line ALK-positive lung cancer.
Entrectinib (Rozlytrek) is a pill for NTRK-fusion cancers and ROS1 lung cancer that reaches brain metastases.
A blood test that reads a tumour's mutations without a tissue biopsy and is the FDA-approved gateway to several targeted drugs.
Iruplinalkib is Qilu Pharmaceutical's second-generation ALK inhibitor, approved in China in 2023 for ALK-positive non-small-cell lung cancer after crizotinib and in 2024 as first-line treatment.
An ALK inhibitor with the longest disease control ever recorded for a targeted lung cancer pill: 60% progression-free at five years.
A fourth-generation ALK pill that works after lorlatinib and avoids the TRK-related brain side effects; under FDA priority review with a decision due 27 November 2026.
TRI-611 is an experimental protein degrader from TRIANA Biomedicines in phase 2 trials for non-small-cell lung cancer, aimed at ALK.
Adjuvant treatment for lung cancer is now chosen by genotype. A resected ALK-positive tumour is treated with two years of a tablet instead of four cycles of platinum, which is a different life as well as a different outcome.
This is the fusion and immune-marker table for the wild-type minority, the group in which RNA sequencing pays for itself.
Lung cancer in never-smokers is not smokers' lung cancer with the smoking removed; it is a different set of diseases with a different clock. The slow-growing piano subtype in particular is the argument that a screening test aimed at never-smokers would need to look for something other than what low-dose computed tomography was built to find.
The current first choice for ALK-positive lung cancer in most guidelines, and the strongest evidence in solid tumour oncology that a drug can be designed to work inside the brain. Five-year follow-up has since shown the majority of patients still progression-free.
It turned the laboratory prediction into a clinical rule: after a second-generation ALK inhibitor, genotype the tumour, and treat the absence of an ALK mutation as evidence that the cancer has stopped depending on ALK.
It showed the benefit of plasma testing is not only analytical but logistical: it reaches patients who are too unwell, or whose disease is too inaccessible, for a repeat biopsy.
It is the evidence behind running plasma and tissue together at diagnosis rather than in sequence, and the 80% sensitivity figure is the reason a negative plasma result never ends the work-up.
It is the document that defines what a complete lung cancer molecular report looks like, and its asymmetry about plasma, rule in but never rule out, is the single most useful sentence in it.
Query for this target: (TITLE:"ALK" OR ABSTRACT:"ALK") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about ALK, not a curated reading list.
Shares Iruplinalkib, Dong-Wan Kim, LUNGevity Foundation (and GO2 for Lung Cancer), ROS1 rearrangements define a unique molecular class of lung cancers and the tags driver, kinase.
Shares Justin F. Gainor, Imagene AI, Lucence, Sequence: targeted therapy before immunotherapy in driver-positive NSCLC and the tags driver, kinase.
Shares Lemmon and Schlessinger 2010: cell signalling by receptor tyrosine kinases, LUNGevity Foundation (and GO2 for Lung Cancer), Aichi Cancer Center, Shanghai Pulmonary Hospital and the tags driver, kinase.
Shares Imagene AI, Oncogene, Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic non-small cell lung cancer, Test intermittent dosing of targeted drugs to delay resistance, with honest priors and the tags driver, kinase.
Shares Oncogene, Hallmark: sustaining proliferative signalling, Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs, Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms and the tags driver, kinase.
Shares Molecular characterization of KRAS wild-type tumors in patients with pancreatic adenocarcinoma, KRAS wild-type pancreatic ductal adenocarcinoma, Gene fusion, PI3K / AKT / mTOR and the tags driver, kinase.
Shares Lemmon and Schlessinger 2010: cell signalling by receptor tyrosine kinases, PI3K / AKT / mTOR, Receptor tyrosine kinase activation, RAS / RAF / MEK / ERK (MAPK) and the tags driver, kinase.
Shares Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall, Receptor tyrosine kinase activation, Small-molecule kinase inhibitors and the tags driver, kinase.