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Since the discovery of mutationally activated RAS in human cancers, small molecule inhibitors have been long sought but disappointingly elusive. RAS is in an inactive, “off” state when bound to guanosine diphosphate (GDP) and in an active, “on” state when bound to guanosine triphosphate (GTP). According to dogma, mutationally activated RAS is insensitive to GTPase activating proteins (GAPs) that accelerate conversion of active GTP-bound RAS to inactive, GDP-bound RAS. Yet, a small molecule blocks the growth of cancer cells expressing a KRAS Gly(12)→Cys (KRAS(G12C)) mutant, despite binding only GDP-bound KRAS(G12C) (1). The US Food and Drug Administration recently approved sotorasib, a KRAS(G12C) off inhibitor, and more are in the pipeline. How can there be sufficient GDP-bound KRAS(G12C) to enable inhibitor efficacy? On page 197 of this issue, Li et al. (2) find that a GAP for heterotrimeric Gα subunits can also promote GTP hydrolysis to stimulate formation of GDP-bound KRAS(G12C).

KRAS GTPases are activated in one-third of cancers, and KRAS(G12C) is one of the most common activating alterations in lung adenocarcinoma

The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of an amplification in the BRAF oncogene (BRAF