Targeting KRAS codon 13 mutations using direct combination approaches in non-small cell lung cancer

Direct inhibitors of KRASG12C are now used as standard-of-care therapy in KRASG12C-mutant non-small cell lung cancer (NSCLC), but less is understood about the molecular mechanisms and consequent treatment vulnerabilities of KRAS codon 13 mutations in this setting. Here we characterized tumorigenic properties of NSCLC harboring KRASG13X in a large multi-national cohort of NSCLC patients and in preclinical models of KRASG13X NSCLC. Induction of KRASG13C or KRASG13D expression confers reduced oncopotency compared to allele-specific controls affecting KRAS codon 12, particularly KRASG13C. We identified functionally relevant co-mutations in KRASG13X NSCLC, including KEAP1, STK11, BRAF and NF1. The novel RAS(ON) G13C-selective inhibitor, RMC-8839, reduces viability in a panel of KRASG13C NSCLC cell models. To determine combination partners that enhance RAS(ON) mutant-selective inhibition, a drug repurposing screen revealed that KRASG13C models are selectively vulnerable to chemotherapy. Combination of docetaxel with RMC-8839 demonstrated robust anti-proliferative activity in KRASG13C-driven NSCLC models in vitro and in vivo.