Mitogen-activated protein kinase kinase (MEK) (MEK)

Mitogen-activated protein kinase kinase (MEK), specifically the isoforms MEK1 and MEK2, is a central node in the highly conserved RAS-RAF-MEK-ERK signaling pathway. This pathway transmits extracellular signals from cell surface receptors to the nucleus, where it regulates critical cellular functions including growth, proliferation, differentiation, and survival (UniProt Q02750, P36507). In various malignancies, such as melanoma and colorectal cancer, the MAPK pathway is frequently hyperactivated by oncogenic mutations in upstream components like BRAF or RAS (PubMed: 17700604). MEK serves as an attractive therapeutic target because it is the sole known activator of ERK1 and ERK2, making it a bottleneck in the signaling cascade (PubMed: 22197102). Pharmacological MEK inhibitors, which are typically non-ATP-competitive allosteric inhibitors, have been developed to block this pathway and are often used in combination with BRAF inhibitors to delay the onset of drug resistance and improve clinical outcomes (Nature Reviews Cancer: 15, 577–592). These inhibitors are also utilized in treating RASopathies, such as neurofibromatosis type 1, where they help manage plexiform neurofibromas (NIH: Selumetinib). Despite their clinical efficacy, MEK inhibitors are associated with a distinct profile of adverse events, including dermatologic toxicities and ocular changes like serous retinopathy (StatPearls: MEK Inhibitors). Monitoring for these side effects and the presence of specific genetic biomarkers is essential for optimizing patient outcomes during therapy.

Other names

MAP2KMAPKKMKKMAP kinase kinaseDual specificity mitogen-activated protein kinase kinase

Allosteric inhibition of MEK1 and MEK2, preventing the phosphorylation and subsequent activation of downstream extracellular signal-regulated kinases (ERK1/2).