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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.
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.
In plain words · 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.
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.
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.
6 products aim at MEK1/2: cell therapies and small molecules. Kinases are switched on by binding ATP inside the cell, so most drugs are small molecules shaped to plug that ATP pocket.
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.)
Sources: Human Protein Atlas MAP2K1 tissue; Human Protein Atlas MAP2K2 tissue; Open Targets ENSG00000169032 associations; Open Targets ENSG00000126934 associations
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.
RNA: low tissue specificity, detected in all normal tissues.
No normal tissue stained high; medium in Adrenal gland, Appendix, Caudate, Cerebral cortex, Colon, Duodenum and more.
No cancer stained high; medium in breast cancer, carcinoid, cervical cancer, colorectal cancer.
HPA MAP2K1 tissue · HPA MAP2K1 pathology · HPA protein class: FDA approved drug targets
RNA: low tissue specificity, detected in all normal tissues.
Medium: Adrenal gland, Breast, Bronchus, Caudate, Cerebral cortex, Cervix, Gallbladder, Kidney.
Medium only: cervical cancer, endometrial cancer, lung cancer, ovarian cancer.
HPA MAP2K2 tissue · HPA MAP2K2 pathology · HPA protein class: 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 |
|---|---|---|---|---|
| Langerhans cell histiocytosis | 27.5% | Somatic MAP2K1 mutation, 11 of 40 cases, mutually exclusive with BRAF V600E | Found in half of BRAF wild-type cases; the basis for MEK inhibitor use in histiocytosis | doi.org |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Atebimetinib is an experimental small-molecule drug from Immuneering in phase 3 trials for pancreatic ductal adenocarcinoma, aimed at MEK1/2.
GC101 TIL is an experimental tumour-infiltrating lymphocyte therapy from Shanghai Juncell Therapeutics in phase 2 trials for melanoma, aimed at PD-1 and BRAF.
Mirdametinib (Gomekli in the US, Ezmekly in Europe) is a MEK-blocking capsule or dispersible tablet for adults and children with neurofibromatosis type 1 whose plexiform neurofibromas cannot be removed surgically; it is the first such drug approved for adults.
Selumetinib (Koselugo) is the first medicine for children and adults with neurofibromatosis type 1 whose plexiform neurofibromas, benign but disfiguring and painful nerve tumours, cannot be removed by surgery.
Trametinib (Mekinist) blocks MEK, the protein one step below BRAF in the growth-signal chain. Paired with dabrafenib it treats BRAF-mutant melanoma, lung, thyroid and other cancers, including brain tumours in children.
Tunlametinib is a Chinese MEK inhibitor approved in 2024 for advanced melanoma with an NRAS mutation, a group with no targeted therapy elsewhere in the world, and in phase 3 trials with vemurafenib for BRAF-mutant disease and for colorectal cancer.
Query for this target: (TITLE:"MEK1/2" OR ABSTRACT:"MEK1/2" OR TITLE:"MAP2K1" OR ABSTRACT:"MAP2K1" OR TITLE:"MAP2K2" OR ABSTRACT:"MAP2K2") 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 MEK1/2, not a curated reading list.
Shares Chronic myeloid leukaemia (KEGG map), Melanoma (KEGG map), Acute myeloid leukaemia (KEGG map), Non-small cell lung cancer (KEGG map) and the tag kinase.
Shares Melanoma (KEGG map), Bladder cancer (KEGG map), Breast cancer (KEGG map), Non-small cell lung cancer (KEGG map) and the tag kinase.
Shares Epithelioid haemangioendothelioma and the tag kinase.
Shares GC101 TIL, CRAF (RAF1), coBRIM, COMBI-d and the tag kinase.
Shares Acute myeloid leukaemia (KEGG map), Acral melanoma, Mucosal melanoma, RAS / RAF / MEK / ERK (MAPK) and the tag kinase.
Shares Thyroid cancer (KEGG map), Non-small cell lung cancer (KEGG map), Thyroid cancer, RAS / RAF / MEK / ERK (MAPK) and the tag kinase.
Shares Paediatric high-grade glioma (excluding diffuse midline glioma), RAS / RAF / MEK / ERK (MAPK), Non-small-cell lung cancer and the tag kinase.
Shares Paediatric high-grade glioma (excluding diffuse midline glioma), Non-small cell lung cancer (KEGG map), RAS / RAF / MEK / ERK (MAPK), Colorectal cancer and the tag kinase.