ALK

Overview

ALK is a receptor tyrosine kinase recurrently activated by gene fusions in multiple cancer types, including histiocytic neoplasms where it provides a targetable driver alteration.

Alterations observed in the corpus

  • TFG-ALK fusion identified in one histiocytosis patient profiled on MSK-IMPACT with targeted RNA sequencing PMID:36862133.
  • ALK fusions cited as a reference class for MAPK-targeted therapy response comparison (60-80% ORR) in a tumor-agnostic BRAF fusion landscape analysis of 97,024 MSK-sequenced samples; BRAF fusions were acquired as resistance mechanisms in some patients after ALK-directed therapy PMID:38922339.
  • EML4::ALK fusions were detected in CSF ctDNA from lung carcinoma patients with CNS involvement in the csf_msk_2024 cohort (1,007 CSF samples, 711 patients); ALK resistance mutations p.G1202R and p.G1269A were detected upon targeted therapy progression PMID:39289779.
  • ALK significantly over-expressed in the undifferentiated nC3 cluster of high-risk neuroblastoma tumors; co-expressed with MYCN in discrete tumor regions (validated by RNAscope in sample K10); nC3 over-expression confirmed at FDR < 0.01 by Welch’s t-test across 11 single-nuclei tumor specimens PMID:34493726.
  • EML4-ALK translocation status (FISH) was annotated for 196/211 resected early-stage NSCLC patients in the Stanford NSCLC-Radiogenomics cohort as part of a paired radiogenomic dataset; per-subject status is provided as a data record rather than aggregate frequencies PMID:30325352.
  • ALK fusion in 6% of advanced NSCLC immunotherapy cohort; included in multivariate model for PFS PMID:36038778
  • ALK inhibitor sensitivity profiled across cancer cell lines in the Cancer Cell Line Encyclopedia (CCLE), linking ALK alterations to drug response PMID:22460905
  • Recurrently mutated in neuroblastoma (Broad WES/WGS, 240 tumors); ALK point mutations and amplifications found as key oncogenic drivers in neuroblastoma PMID:23334666
  • ALK-fusion lung cancer treated with crizotinib is cited as a resistance analogy in HCC targeted therapy — acquired resistance is expected and motivates combination regimens PMID:24735922
  • Fusions detected in 3/230 (1.3%) LUAD cases; restricted to the transversion-low subgroup; represents a clinically actionable RTK/RAS/RAF pathway alteration in oncogene-defined LUAD PMID:25079552
  • Fusions in 0.8% (4/484) of papillary thyroid carcinomas, including EML4/ALK; fusion-positive tumors characterized by younger age and are a potential targetable alteration PMID:25417114
  • ALK somatic mutations detected in 7/56 (12.5%) WGS neuroblastoma cases, distributed across both high-risk and low-risk groups — not specific to the high-risk telomere-maintenance biology defined by TERT rearrangement, MYCN amplification, or ATRX mutation PMID:26466568
  • ALK fusions detected in 3 PDTC cases involving partners STRN, EML4, and a novel CCDC149 partner; mutually exclusive with BRAF, RAS, TSHR, and STK11 mutations; PDTCs with fusions were younger (median 49 vs 58 years, P = 0.04) PMID:26878173
  • ALK fusion inhibitors cited as subtype-specific targeted therapies applicable exclusively to lung ADC; ALK/ROS1 inhibitors expected to have no role in lung SqCC given histology-restricted driver landscape PMID:27158780
  • ALK rearrangements (most often EML4-ALK, >80% of cases) over-represented in young lung cancer (YLC); targetable with crizotinib and lorlatinib PMID:27346245
  • TPM3–ALK fusion identified in a uRCC case (T12), marking an emerging RCC entity and raising the possibility of ALK inhibitor therapy in molecularly selected cases PMID:27713405
  • ALK Q1146K activating mutation identified in adrenocortical carcinoma (ACC) in a pediatric pan-cancer sequencing cohort; ALK-inhibitor therapy initiated PMID:28007021
  • ALK mutation enriched in HR+/HER2- metastatic breast cancer (mBC) at FDR<0.1 — potentially actionable but functional consequences require further characterization PMID:28027327
  • ALK fusions (level 1) in LUAD; high matched-therapy uptake (93%) and benefit (85.8%); two ROS1-fusion patients died before crizotinib FDA approval in March 2016 PMID:28336552
  • Kinase fusions enriched in LUAD but also detected across 11 additional tumor types; EML4-ALK fusion in n=38 predominantly LUAD, part of the pan-cancer MSK-IMPACT profiling dataset (n=10,945 consecutive patients) PMID:28481359
  • Activating ALK fusions identified with novel partners in MET500 pan-cancer metastatic cohort (500 patients), expanding the targetable fusion landscape beyond canonical contexts PMID:28783718
  • ALK rearrangements observed at low frequency (~1%) in a 240-patient NSCLC ICI cohort; too few events for response analysis PMID:29337640.
  • ALK cited as a comparator oncogenic driver with approved targeted therapies achieving higher response rates than neratinib in HER2-mutant disease in the SUMMIT basket trial PMID:29420467.
  • EML4–ALK and other ALK fusions were detected in 20 samples across 8 cancer types (5 in LUAD) in a pan-cancer TCGA fusion analysis; EML4 is the most frequent 5’ partner (7/17), and fusion status corresponds to copy-number-neutral ALK overexpression — rationale for crizotinib and other ALK inhibitors. PMID:29617662

Cancer types (linked)

  • Histiocytosis (LCH/ECD) — ALK fusions are a rare but actionable driver class within the broader MAPK/kinase-driven histiocytosis landscape PMID:36862133.
  • NSCLC — EML4::ALK fusions detected in CSF ctDNA from lung carcinoma patients with CNS tumors; resistance mutations p.G1202R and p.G1269A emerged on targeted therapy PMID:39289779.
  • Neuroblastoma (NBL) — ALK over-expression marks the undifferentiated high-risk nC3 cluster enriched in MYCN-amplified and/or 11q-deleted tumors; serves as a transcriptional biomarker differentiating high-risk from low-risk disease PMID:34493726.

Co-occurrence and mutual exclusivity

  • Within histiocytosis, ALK fusions co-classify with BRAF, MAP2K1, KRAS, CSF1R, and NTRK1 as the set of potentially actionable kinase-pathway drivers PMID:36862133.
  • In neuroblastoma, ALK over-expression co-occurs with MYCN amplification and NTRK2 over-expression in the high-risk nC3 cluster; mutually exclusive with the NTRK1-high, low-risk noradrenergic clusters PMID:34493726.

Therapeutic relevance

  • ALK fusions in histiocytosis are candidates for matched targeted therapy through the Make-an-IMPACT direct-to-patient program, in which 17/18 histiocytosis patients who received genomically matched therapy had clinical benefit (mean duration 21.7 months) PMID:36862133.
  • Serial CSF ctDNA profiling identified emergence of ALK resistance mutations (p.G1202R, p.G1269A) in EML4::ALK-positive NSCLC patients, directly informing treatment changes PMID:39289779.

Open questions

  • Whether ALK-fusion histiocytosis responds durably to ALK inhibitors is not directly evaluated in the corpus PMID:36862133.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:36038778

This page was processed by crosslinker on 2026-05-14. - PMID:22460905

This page was processed by crosslinker on 2026-05-14. - PMID:23334666

This page was processed by crosslinker on 2026-05-14. - PMID:24735922

This page was processed by crosslinker on 2026-05-14. - PMID:25079552

This page was processed by crosslinker on 2026-05-14. - PMID:25417114

This page was processed by crosslinker on 2026-05-14. - PMID:26466568

This page was processed by crosslinker on 2026-05-14. - PMID:26878173

This page was processed by entity-page-writer on 2026-05-15. - PMID:27158780

This page was processed by entity-page-writer on 2026-05-15. - PMID:28007021

This page was processed by entity-page-writer on 2026-05-15. - PMID:28027327

This page was processed by entity-page-writer on 2026-05-15. - PMID:28336552

This page was processed by wiki-cli on 2026-05-14. - PMID:28481359

This page was processed by entity-page-writer on 2026-05-15. - PMID:28783718

This page was processed by wiki-cli on 2026-05-15. - PMID:29337640

This page was processed by wiki-cli on 2026-05-15. - PMID:29420467

This page was processed by wiki-cli on 2026-05-15. - PMID:29617662

This page was processed by wiki-cli on 2026-05-15.