{"entity":{"id":"mek","kind":"target","name":"MEK1/2","aka":[],"tldr":"MEK is the relay in the growth-signal chain that sits just below RAS and RAF. Blocking it starves BRAF- and RAS-driven tumours of their go signal.","summary":"Mitogen-activated protein kinase kinases 1 and 2 (MEK1/2, genes MAP2K1 and MAP2K2) are dual-specificity kinases that phosphorylate and activate ERK1/2, the final step of the RAS-RAF-MEK-ERK cascade. They are rarely mutated in cancer themselves but are the pathway's narrowest point, so allosteric MEK inhibitors (trametinib, cobimetinib, binimetinib, selumetinib, mirdametinib) are used with BRAF inhibitors in BRAF V600 melanoma, NSCLC and thyroid cancer, alone in NF1 plexiform neurofibromas and low-grade glioma, and with encorafenib in BRAF-mutant colorectal cancer. Paradoxical pathway reactivation and adaptive feedback limit single-agent activity in RAS-mutant tumours.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/MAP2K1","links":[{"label":"NCBI Gene MAP2K1","url":"https://www.ncbi.nlm.nih.gov/gene/5604"},{"label":"NCBI Gene MAP2K2","url":"https://www.ncbi.nlm.nih.gov/gene/5605"}],"tags":["kinase"],"related":[],"cancers":["melanoma","nsclc","thyroid","colorectal"],"sections":[],"technologies":[],"targets":[],"drugs":["mirdametinib","atebimetinib","gc101-til"],"companies":[],"institutions":[],"pathways":["ras-mapk","aml-signalling","bladder-cancer-signalling","breast-cancer-signalling","cml-signalling","melanoma-signalling","nsclc-signalling","thyroid-cancer-signalling"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Prevalence not recorded as a positivity rate: MEK1/2 are ubiquitously expressed and MEK inhibitors are selected on upstream BRAF V600 (or NF1/RAS) status, not on MEK itself. MAP2K1/MAP2K2 mutations are recurrent but uncommon: Nikolaev 2012 reported an overall frequency of 8% in melanoma without a denominator in the abstract (doi:10.1038/ng.1026), and Hodis 2012 lists MAP2K1 among 11 significantly mutated genes in 121 melanomas without a per-gene rate in the main text (doi:10.1016/j.cell.2012.06.024); no series with a stated denominator was found for NSCLC, thyroid or colorectal cancer."],"symbol":"MAP2K1, MAP2K2","role":[],"sources":[],"specificity":"broadly-expressed","distribution":"many-types","tumourAgnostic":true,"specificityNote":"Broadly expressed or essential: HPA finds the RNA at low tissue specificity; the 6 medicines aimed at it (Mirdametinib, Atebimetinib, GC101 TIL and more) act on the wild-type protein, so normal tissue is exposed and the therapeutic window comes from the tumour's faster division or its dependence on the protein. HPA MAP2K1: RNA low tissue specificity; no normal tissue stained high. HPA MAP2K2: RNA low tissue specificity; high antibody staining in 21 normal tissues; highest cancer staining thyroid cancer (4 of 4 high). Distribution: 5 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Langerhans cell histiocytosis (LCH), Skin cancer (all types), Lung cancer (all types), Thyroid cancer, Colorectal cancer); approvals of single-target medicines aimed at it also list Ovarian cancer, Brain and spinal cord tumours (all types), not counted; Open Targets associates it with 4 specific cancer types at or above 0.5 (melanoma, neurofibromatosis type 1, cutaneous melanoma, plexiform neurofibroma). Tissue-agnostic: Trametinib US 2014: \"With dabrafenib: metastatic melanoma; later adjuvant melanoma, NSCLC, anaplastic thyroid cancer, tumour-agnostic BRAF V6\". (Rule 7 of scripts/fetch-target-specificity.ts.)","specificitySources":[{"label":"Human Protein Atlas MAP2K1 tissue","url":"https://www.proteinatlas.org/ENSG00000169032-MAP2K1/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Human Protein Atlas MAP2K2 tissue","url":"https://www.proteinatlas.org/ENSG00000126934-MAP2K2/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000169032 associations","url":"https://platform.opentargets.org/target/ENSG00000169032/associations","note":"cancer associations at or above 0.5 (CC0)"},{"label":"Open Targets ENSG00000126934 associations","url":"https://platform.opentargets.org/target/ENSG00000126934/associations","note":"cancer associations at or above 0.5 (CC0)"}],"biology":"Allosteric (non-ATP-competitive) inhibitors lock MEK in an inactive conformation. Toxicities reflect on-target ERK inhibition in normal tissue: rash, diarrhoea, retinal changes (central serous retinopathy), and reduced ejection fraction.","whereFound":["BRAF V600 melanoma (as combination partner)","NF1-associated plexiform neurofibroma","BRAF V600E NSCLC and anaplastic thyroid cancer","Paediatric low-grade glioma","Histiocytic neoplasms"],"targetClass":"kinase","prevalence":[{"cancerId":"langerhans-cell-histiocytosis","pct":27.5,"measure":"Somatic MAP2K1 mutation, 11 of 40 cases, mutually exclusive with BRAF V600E","source":"https://doi.org/10.1182/blood-2014-05-577361","note":"Found in half of BRAF wild-type cases; the basis for MEK inhibitor use in histiocytosis"}]},"route":"/targets/mek/","neighbours":{"cancer":[{"id":"acral-melanoma","kind":"cancer","name":"Acral melanoma","route":"/cancers/acral-melanoma/"},{"id":"braf-v600-melanoma","kind":"cancer","name":"BRAF V600-mutant melanoma","route":"/cancers/braf-v600-melanoma/"},{"id":"braf-v600e-colorectal","kind":"cancer","name":"BRAF V600E-mutant colorectal cancer","route":"/cancers/braf-v600e-colorectal/"},{"id":"brain-tumours","kind":"cancer","name":"Brain and spinal cord tumours (all types)","route":"/cancers/brain-tumours/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"epithelioid-haemangioendothelioma","kind":"cancer","name":"Epithelioid haemangioendothelioma","route":"/cancers/epithelioid-haemangioendothelioma/"},{"id":"malignant-peripheral-nerve-sheath-tumour","kind":"cancer","name":"Malignant peripheral nerve sheath tumour (MPNST)","route":"/cancers/malignant-peripheral-nerve-sheath-tumour/"},{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"},{"id":"mucosal-melanoma","kind":"cancer","name":"Mucosal melanoma","route":"/cancers/mucosal-melanoma/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"paediatric-high-grade-glioma","kind":"cancer","name":"Paediatric high-grade glioma (excluding diffuse midline glioma)","route":"/cancers/paediatric-high-grade-glioma/"},{"id":"skin-cancer","kind":"cancer","name":"Skin cancer (all types)","route":"/cancers/skin-cancer/"},{"id":"thyroid","kind":"cancer","name":"Thyroid cancer","route":"/cancers/thyroid/"}],"drug":[{"id":"atebimetinib","kind":"drug","name":"Atebimetinib","route":"/drugs/atebimetinib/"},{"id":"gc101-til","kind":"drug","name":"GC101 TIL","route":"/drugs/gc101-til/"},{"id":"mirdametinib","kind":"drug","name":"Mirdametinib","route":"/drugs/mirdametinib/"},{"id":"selumetinib","kind":"drug","name":"Selumetinib","route":"/drugs/selumetinib/"},{"id":"trametinib","kind":"drug","name":"Trametinib","route":"/drugs/trametinib/"},{"id":"tunlametinib","kind":"drug","name":"Tunlametinib","route":"/drugs/tunlametinib/"}],"pathway":[{"id":"aml-signalling","kind":"pathway","name":"Acute myeloid leukaemia (KEGG map)","route":"/pathways/aml-signalling/"},{"id":"bladder-cancer-signalling","kind":"pathway","name":"Bladder cancer (KEGG map)","route":"/pathways/bladder-cancer-signalling/"},{"id":"breast-cancer-signalling","kind":"pathway","name":"Breast cancer (KEGG map)","route":"/pathways/breast-cancer-signalling/"},{"id":"cml-signalling","kind":"pathway","name":"Chronic myeloid leukaemia (KEGG map)","route":"/pathways/cml-signalling/"},{"id":"melanoma-signalling","kind":"pathway","name":"Melanoma (KEGG map)","route":"/pathways/melanoma-signalling/"},{"id":"nsclc-signalling","kind":"pathway","name":"Non-small cell lung cancer (KEGG map)","route":"/pathways/nsclc-signalling/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"},{"id":"thyroid-cancer-signalling","kind":"pathway","name":"Thyroid cancer (KEGG map)","route":"/pathways/thyroid-cancer-signalling/"}],"trial":[{"id":"beacon-crc","kind":"trial","name":"BEACON CRC","route":"/trials/beacon-crc/"},{"id":"checkmate-142","kind":"trial","name":"CheckMate 142","route":"/trials/checkmate-142/"},{"id":"cobrim","kind":"trial","name":"coBRIM","route":"/trials/cobrim/"},{"id":"combi-d","kind":"trial","name":"COMBI-d","route":"/trials/combi-d/"},{"id":"imblaze370","kind":"trial","name":"IMblaze370","route":"/trials/imblaze370/"}],"paper":[{"id":"paper-bluemn-double-negative-prostate-fgf-mapk-cancer-cell-2017","kind":"paper","name":"Androgen receptor pathway-independent prostate cancer is sustained through FGF signalling","route":"/key-papers/paper-bluemn-double-negative-prostate-fgf-mapk-cancer-cell-2017/"}],"target":[{"id":"raf1","kind":"target","name":"CRAF (RAF1)","route":"/targets/raf1/"},{"id":"fak","kind":"target","name":"FAK (PTK2)","route":"/targets/fak/"},{"id":"nf1","kind":"target","name":"NF1 (neurofibromin)","route":"/targets/nf1/"},{"id":"nras","kind":"target","name":"NRAS","route":"/targets/nras/"}],"company":[{"id":"pierre-fabre","kind":"company","name":"Pierre Fabre","route":"/companies/pierre-fabre/"}]}}