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

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.