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

RMC-8839, a RAS(ON) G13C-selective covalent tri-complex inhibitor, caused tumor regressions in selected KRAS G13C-mutant xenografts and revealed incomplete pathway suppression in one-third of cell lines.

• Why it matters: Many RAS-mutant cancers still lack targeted options, and incomplete RAS pathway shutdown despite strong KRAS G13C engagement suggests compensatory signaling by wild-type RAS(ON) isoforms.
• What they did: The study used RMC-8839 in KRAS G13C-mutant xenograft models and tested in vitro pathway suppression versus KRAS G13C engagement; it also characterized codon 13 RAS biochemistry and assessed enrichment of co-occurring RAS pathway mutations.
• The result: Codon 13-mutant RAS showed decreased stability, increased nucleotide exchange, and substantial intrinsic and GAP-stimulated GTP hydrolysis, while codon 13 tumors were enriched for mutations increasing wild-type RAS activation; combining RMC-8839 with a RAS(ON) multi-selective inhibitor produced deeper xenograft growth inhibition than either agent alone.

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