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. In this study, we characterized the tumorigenic properties of NSCLC harboring KRASG13X in a large multinational cohort of patients with NSCLC and in preclinical models of KRASG13X NSCLC. Induction of KRASG13C or KRASG13D expression confers reduced oncopotency compared with allele-specific controls affecting KRAS codon 12, particularly KRASG13C. We identified functionally relevant comutations 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 antiproliferative activity in KRASG13C-driven NSCLC models in vitro and in vivo. Significance: We characterize the second most common KRAS mutational hotspot in NSCLC after codon 12, KRASG13X, from tumor initiation to advanced disease. KRASG13C is a novel, directly targetable subset of NSCLC, with vulnerability to the combination of chemotherapeutics and the mutant-selective RAS(ON) inhibitor RMC-8839, a finding immediately relevant to patient care. See related commentary by Araujo and Skoulidi, p. 2206 See related article by Seamon et al., p. 2256

Supplementary Table 1 - Baseline characteristics of RAS-PM patients. Supplementary Table 2 - Treatment information for RAS-PM patients. Supplementary Table 3 - Number of patients tested for each co-mutation within RAS-PM, independently of treatment regimen. Supplementary Table 4 – Antibodies.

TCGA LUAD immune gene signatures based on KRAS-mutant genotype

List of compound library screen drugs