Selective Inhibition of KRASG13C Reveals an Increased Dependence on Wild-Type RAS Isoforms in Codon 13 RAS-Mutant...

Covalent KRAS G12C inhibitors have changed the treatment landscape for NSCLC and CRC patients, but numerous RAS-mutant cancers lack approved targeted therapies. Here we describe RMC-8839, an oral RAS(ON) G13C-selective, covalent, tri-complex inhibitor that induced tumor regressions in selected KRAS G13C-mutant xenograft models. However, one-third of KRAS G13C-mutant human cancer cell lines in vitro showed incomplete RAS pathway suppression despite near-complete KRAS G13C engagement, suggesting a role for wild-type RAS(ON). We find that codon 13-mutant RAS differs from other KRAS mutations, exhibiting decreased stability, increased nucleotide exchange, and substantial intrinsic and GAP-stimulated GTP hydrolysis, which decreases oncogenicity. Furthermore, co-occurring RAS pathway mutations leading to increased wild-type RAS activation are enriched in codon 13 mutant tumors. Consistent with a role for wild-type RAS(ON) signaling, combination of RMC-8839 with a RAS(ON) multi-selective inhibitor resulted in deeper inhibition of KRAS G13C-mutant xenograft tumor growth than either inhibitor alone.