Figure 1.

The promise of KRAS G12C inhibitors. Compared with wild-type KRAS, cysteine 12 (C12) mutations destroy the GTPase activity of KRAS and lock it in the GTP-bound state. Once activated, Ras signals through 80 effectors, thus activating many different signaling pathways involved in cell proliferation, survival, metabolism, and migration. The best-characterized pathways are the MAPK (Raf-MEK-ERK), PI3K/AKT, and Ral pathways. In contrast, the small molecule drugs sotorasib and adagrasib can form a covalent bond with C12 in the KRAS-G12C protein, causing KRAS to take on an inactive state.