MEK1/2

Class

Selective oral MEK1/2 inhibitor (FCN-159)

Pathway

blocks MEK1/2 in the RAS/RAF/MEK/ERK pathway, used in NF1/NF2-related tumors, pediatric low-grade glioma with BRAF alterations, Langerhans cell histiocytosis, and KRAS-mutant NSCLC

MEK1 and MEK2 are closely related enzymes (kinases) that sit in the middle of the RAS/RAF/MEK/ERK signaling cascade, a chain of molecular relays that cells use to interpret growth signals and decide whether to divide, differentiate, or survive. This pathway is frequently switched on inappropriately in tumors, either through mutations in upstream components such as RAS or RAF, or through loss of regulatory proteins like neurofibromin (the product of the NF1 gene) that normally keep the pathway in check. Because MEK acts as a convergence point downstream of many different upstream lesions, blocking it can shut down excessive pathway activity regardless of which upstream alteration caused it. This rationale underlies interest in MEK inhibitors across a range of conditions where RAS/RAF/MEK/ERK signaling drives tumor growth, including neurofibromatosis-associated tumors, certain pediatric low-grade gliomas carrying BRAF alterations, Langerhans cell histiocytosis, and RAS-mutant lung cancers. Selective oral MEK1/2 inhibitors are designed to be taken by mouth and to act specifically on these two kinases, sparing other kinases and reducing some off-target effects. Because the pathway is also active in normal tissues, modulating it carries the inherent challenge of separating therapeutic suppression in tumor cells from disruption of normal cellular signaling.