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Patricelli, Janes, and colleagues identified a small-molecule covalent inhibitor of mutant KRASG12C, ARS-853, that selectively bound to the GDP-bound, inactive protein and prevented formation of the GTP-bound state. ARS-853 blocked downstream mutant KRAS–driven signaling via the MAPK and PI3K pathways and inhibited the growth of KRASG12C-mutant cells. KRASG12C rapidly cycled its nucleotide state, allowing for effective binding of ARS-853, and KRASG12C-GTP levels were regulated by upstream signaling factors, suggesting that combined targeting of upstream activators may enhance the efficacy of single-agent KRASG12C inhibition. These findings indicate that ARS-853 blocks oncogenic KRASG12C signaling and has promise as a potential therapeutic for KRASG12C-mutant cancer. For details, please see the article by Patricelli, Janes, and colleagues on page 316.