Targeting MEK in cancer and beyond: mechanistic insights and therapeutic opportunities

MEK inhibitors are established therapies in BRAF-driven cancers, yet their broader clinical effect is limited by toxicity, resistance, and modest durability as a monotherapy, particularly in RAS-mutant tumours. Dose intensity is often restricted by severe adverse effects, particularly dermatological, gastrointestinal, ocular, and cardiopulmonary toxic effects. Predictive biomarkers, such as tumour mutational burden, interferon signatures, and MAPK pathway activity, are emerging as crucial tools for refining patient selection and monitoring therapeutic response. Advances in drug design, including dual-targeting strategies, aim to expand the therapeutic window and overcome resistance mechanisms. Combination regimens, particularly those incorporating immune checkpoint inhibitors or PI3K-mTOR pathway inhibition, show promise for enhancing efficacy and treatment durability. Beyond oncology, MEK pathway modulation is under investigation in fibrotic, inflammatory, and developmental disorders, although clinical validation remains at an early stage. Building on more than a decade of use in BRAF^V600 (ie, Val600)-mutant melanoma, MEK inhibitors continue to be refined through biomarker-guided combination strategies and exploration in additional cancers and non-oncological diseases.