MEK

MEK (mitogen-activated protein kinase kinase) refers primarily to MEK1 and MEK2, central signaling proteins in the RAF–MEK–MAPK pathway. MEK is activated by RAF, including BRAF and ARAF, and functions as a key downstream node regulating cellular responses relevant to tumor biology. Its position in the pathway makes it a mutation-agnostic therapeutic target in RAS/MAPK-driven tumors, including melanoma, low-grade glioma, biliary tract cancer, and non-small cell lung cancer. MEK activity is also studied in treatment resistance, including resistance associated with BRAF fusions and drug-resistant melanoma.

Pharmacological MEK inhibition is achieved by agents such as trametinib and cobimetinib, which are being evaluated alone and in combinations with BRAF-directed therapy, EGFR inhibition, immunotherapy, or other targeted drugs such as the Aurora kinase A inhibitor alisertib. Allosteric MEK inhibitors can bind RAF–MEK complexes and prevent RAF-mediated MEK activation; newer approaches include RAF-aware and covalent ARAF–MEK inhibitor designs intended to improve selectivity and the therapeutic index. Clinical investigations also include the MEK1/2 inhibitor EDV2209 in spontaneous subarachnoid hemorrhage and nanoparticle delivery systems for combination treatment. Although MEK inhibition has therapeutic potential, pathway reactivation and on-target, off-tissue toxicity remain important limitations.