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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                    <jats:p>See related commentary by Araujo and Skoulidi, p. 2206<\/jats:p>\n                    <jats:p>See related article by Seamon et al., p. 2256<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-0884","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T13:37:07Z","timestamp":1782135427000},"page":"2274-2297","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting\n                    <i>KRAS<\/i>\n                    Codon 13 Mutations Using Direct Combination Approaches in Non\u2013Small Cell Lung 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