Targeting KRAS Codon 13 Mutations Using Direct Combination Approaches in Non-Small Cell Lung Cancer.

RMC-8839 selectively reduces viability in KRASG13C-mutant non-small cell lung cancer models, and combining it with docetaxel shows robust anti-proliferative activity in KRASG13C-driven in vitro and in vivo settings.

• Why it matters: KRAS codon 13 mutations are less understood than KRASG12C, leaving unclear their molecular mechanisms and treatment vulnerabilities in non-small cell lung cancer.
• What they did: The study profiled tumorigenic properties of KRASG13X NSCLC in a large multi-national patient cohort and preclinical models, then used a drug repurposing screen to find combination partners for RAS(ON) mutant-selective inhibition.
• The result: KRASG13C and KRASG13D expression conferred reduced oncopotency versus allele-specific KRAS codon 12 controls, and KRASG13C models were selectively vulnerable to chemotherapy, with docetaxel plus RMC-8839 producing robust anti-proliferative effects in KRASG13C-driven models.

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