MEK (MAP2K1/2)

Class

Small molecule kinase inhibitor, brain-penetrant (also known as polfurmetinib)

Pathway

RAS/RAF/MEK/ERK signaling

MEK1 and MEK2 (encoded by the genes MAP2G1 and MAP2K2) are enzymes that sit in the middle of the RAS/RAF/MEK/ERK signaling cascade, a chain of molecular relays that cells use to decide when to grow, divide, or survive. In many cancers, mutations in upstream components such as RAS or RAF genes lock this cascade in an active state, driving uncontrolled cell proliferation. Because MEK acts as a converging bottleneck through which nearly all of these upstream signals must pass, blocking it can shut down the pathway regardless of which upstream mutation caused the activation. Small-molecule MEK inhibitors bind to the enzyme and prevent it from activating its downstream partner, ERK, thereby dampening the proliferative signal. Brain-penetrant versions of these drugs are designed to cross the blood-brain barrier, extending the reach of this mechanism to tumors that have spread to, or arise within, the central nervous system. This class of mechanism is relevant across a range of cancers driven by RAS/RAF pathway mutations, including certain skin, lung, and other solid tumors, as well as some genetic syndromes that predispose to tumor formation through the same pathway.