Science 351, 604–608 (2016)

Ras is a small GTPase that cycles between an active GTP-bound and an inactive GDP-bound state in response to upstream signaling effectors. GTPases promote the hydrolysis of GTP, whereas nucleotide exchange factors (GEFs) mediate the exchange of GTP for GDP. Oncogenic forms of Ras such as KRASG12C have constitutive activity presumably due to an inability to undergo GTP hydrolysis. Previous small-molecule screening efforts had identified ARS-853 as a specific inhibitor of KRASG12C but without revealing the exact mechanism. Lito et al. observed that ARS-853 selectively decreased KRAS-GTP levels in KRASG12C mutant lung cancer cells and this correlated with inhibition of Ras effector activation and reduced cell proliferation. Differential scanning fluorimetry analysis revealed that ARS-853 bound specifically to the inactive GDP form of KRASG12C. Genetic and biochemical studies determined that KRASG12C retained basal GTPase activity to cycle from the GTP- to the GDP-bound state and that ARS-853 binding to KRAS-GDP trapped it in the inactive state by preventing its interaction with exchange factors. Inhibition of receptor tyrosine kinases that drive nucleotide exchange shortened the time required for ARS-853 to work and enhanced its potency, suggesting that a combination therapy of ARS-853 with inhibitors of nucleotide exchange could be effective in patients with KRASG12C lung cancers.