MAP2K1

Overview

MAP2K1 (MEK1) is a core MAPK-pathway kinase and an actionable driver in histiocytic neoplasms.

Alterations observed in the corpus

  • Mutated in 13% of histiocytosis cases in the Make-an-IMPACT rare-cancer cohort PMID:36862133.
  • Mentioned in the context of the other-MAPK-mutant PDAC subtype in the MSK 2,336-patient cohort (pdac_msk_2024); the other-MAPK-mutant subtype (3% of PDAC) harbors oncogenic activating alterations in MAPK-pathway genes including MAP2K1, almost exclusively in KRAS-WT tumors (60% vs 7% in KRAS-mutant, P = 1.6×10⁻⁴⁷). PMID:39753968
  • MEK1 (MAP2K1) mutations including R47_E62delinsQ detected at resistance to KRASG12C + EGFR inhibition in CRC PMID:36355783
  • MAP2K1 assessed in gallbladder carcinoma (GBC) genomic landscape study PMID:36228155
  • Identified as a significantly mutated gene (q<=0.2) by InVEx permutation framework in WES of 121 melanoma tumors PMID:22817889
  • Acquired resistance mutations (V60E, G128V, V154I, P124S, P124L) in 45 BRAF V600-mutant melanoma patients receiving RAF/MEK inhibitors; all validated mutants conferred 10–80-fold dabrafenib and 3–20-fold trametinib resistance in A375 cells; pre-treatment G276W and F53Y variants associated with clinical benefit PMID:24265153
  • MAP2K1 mutations (n=2) observed as additional RTK/RAS/RAF pathway alterations in LUAD (n=230 TCGA cohort; 76% of LUAD have a defined RTK/RAS/RAF activating event) PMID:25079552
  • Metastasis-private Q56P mutation confirmed by transfection to hyperactivate ERK signaling at levels comparable to known-activating K57N; A106T verified inactive by Western blot in a paired primary/metastasis CRC cohort PMID:25164765
  • MAP2K1 (MEK1) recurrent significantly mutated gene (SMG) in MAPK pathway in cutaneous melanoma (TCGA 333-sample cohort); nominated as part of the MAPK pathway landscape including BRAF, NRAS, NF1, and RAC1 PMID:26091043
  • P124S/L hotspot mutations in 2 desmoplastic melanoma tumors; identified as a targetable MAPK pathway alteration — small-molecule MEK inhibitors noted as potential therapeutic avenue PMID:26343386
  • Recurrent somatic mutations in n=12 (2.0%) of 538 CLL cases; novel MAPK-pathway CLL driver; enriched in prior-treatment samples; contributes to the 8.7% of CLL with NRAS/KRAS/BRAF/MAP2K1 mutations for which MEK inhibition is proposed PMID:26466571
  • MAP2K1 nominated as a RAS-pathway kinase CRC driver in a 619-tumor whole-exome sequencing study (NHS/HPFS cohort) PMID:27149842
  • MAP2K1 harbors a recurrent in-frame insertion in lung adenocarcinoma identified in pan-lung cancer TCGA analysis (n=1144) PMID:27158780
  • 6 patients with activating alleles (E203K, K57N, Q56P, G128V, E102_I103del) in prospective LUAD cohort (860 patients, MSK-IMPACT); none received matched therapy as highest-level alteration PMID:28336552
  • Hotspot MAPK-pathway missense mutation observed in ~5% of advanced prostate cancer patients across locoregional, metastatic noncastrate, and mCRPC disease states alongside BRAF, HRAS, and KRAS PMID:28825054

Cancer types (linked)

  • LCH / ECD — second most common actionable gene in the histiocytosis sub-cohort (n=84) after BRAF PMID:36862133.
  • PAAD — MAP2K1 and other MAPK-pathway genes (not KRAS) drive the other-MAPK-mutant subtype in KRAS-WT PDAC; these tumors had longer OS vs KRAS-mutant when not receiving targeted therapy (HR_adj = 0.68, P = 0.035). PMID:39753968

Co-occurrence and mutual exclusivity

  • None reported.

Therapeutic relevance

  • MAP2K1-mutant histiocytosis patients were treated with MEK inhibitors trametinib and cobimetinib; one patient received an ERK inhibitor on trial, contributing to the 17/18 (94%) clinical-benefit rate from matched targeted therapy PMID:36862133.
  • In KRAS-WT PDAC, MAP2K1 and other MAPK-pathway activation suggest eligibility for targeted MAPK-pathway therapies; the other-MAPK-mutant subtype’s improved OS was partly driven by access to matched targeted therapy. PMID:39753968

Open questions

  • None noted.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:36355783

This page was processed by crosslinker on 2026-05-14. - PMID:36228155

This page was processed by crosslinker on 2026-05-14. - PMID:22817889

This page was processed by crosslinker on 2026-05-14. - PMID:24265153

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

This page was processed by crosslinker on 2026-05-14. - PMID:25164765

This page was processed by crosslinker on 2026-05-14. - PMID:26091043

This page was processed by crosslinker on 2026-05-14. - PMID:26343386

This page was processed by wiki-cli on 2026-05-14. - PMID:26466571

This page was processed by wiki-cli on 2026-05-14. - PMID:27149842

This page was processed by wiki-cli on 2026-05-14. - PMID:27158780

This page was processed by wiki-cli on 2026-05-14. - PMID:28336552

This page was processed by wiki-cli on 2026-05-14. - PMID:28825054

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