MEK1/2
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.
Overview
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.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
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.
- 1 · What it is
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.
- 2 · What goes wrong in cancer
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.
- 3 · How drugs use it
3 products aim at MEK1/2: small molecules. Kinases are switched on by binding ATP inside the cell, so most drugs are small molecules shaped to plug that ATP pocket.
Elsewhere
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.
- BRAF V600 melanoma (as combination partner)
- NF1-associated plexiform neurofibroma
- BRAF V600E NSCLC and anaplastic thyroid cancer
- Paediatric low-grade glioma
- Histiocytic neoplasms
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.
Latest papers
topQuery 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.
Pages like this
not linked directly; found by shared links- ProductDabrafenib
Shares Trametinib, Thyroid cancer, RAS / RAF / MEK / ERK (MAPK), Melanoma.
- TargetROS1
Shares RAS / RAF / MEK / ERK (MAPK), Non-small-cell lung cancer and the tag kinase.
- TargetRET
Shares Thyroid cancer, RAS / RAF / MEK / ERK (MAPK), Non-small-cell lung cancer and the tag kinase.
- TargetBRAF
Shares Thyroid cancer, RAS / RAF / MEK / ERK (MAPK), Melanoma, Colorectal cancer and the tag kinase.
- TargetKIT
Shares RAS / RAF / MEK / ERK (MAPK), Melanoma and the tag kinase.
- TargetALK
Shares RAS / RAF / MEK / ERK (MAPK), Non-small-cell lung cancer and the tag kinase.
- TargetFGFR2
Shares RAS / RAF / MEK / ERK (MAPK) and the tag kinase.
- TargetEGFR
Shares RAS / RAF / MEK / ERK (MAPK), Colorectal cancer, Non-small-cell lung cancer and the tag kinase.