Abstract A011: Decoding the codons: Uncovering KRAS mutant isoform-specific vulnerabilities in non-small cell lung cancer

Abstract Direct inhibitors of KRASG12C and KRASG12D and other KRAS isoforms represent the beginning of a major translational breakthrough for non-small cell lung cancer (NSCLC) and cancer in general, targeting its most commonly mutated oncogene. However early reports of resistance with these small molecules have highlighted the pressing need for rationale and effective combination partners. To determine such partners, a clearer understanding of KRAS mutant allele-specific biology is critical. Herein, the oncopotency between specific KRAS hotspot mutations on codons 12 and 13 was compared to determine mutant-specific biological properties. Through a comprehensive analysis of genetically engineered mouse models, in vitro models of KRASG12C, KRASG12D, KRASG13C and KRASG13D-driven NSCLC initiation and established tumour cell lines and a patient database, we determined the differences between these mutations in terms of proliferation and immediate signalling and how these phenotypes change over time. Furthermore, using transcriptomic analyses and a compound library screen, we also identified therapeutic vulnerabilities specific to each mutation studied. We further combined the targeting of these vulnerabilities with direct KRAS mutant inhibitors including the KRASG12D inhibitor MRTX1133 and a novel KRASG13C selective inhibitor RMC-8839 and demonstrated highly synergistic combination effects specific to the KRAS mutant allele both in vitro and in vivo. Our data propose unique combination treatment vulnerabilities that suggests patient selection strategies for combination approaches should be both contextualised to individual KRAS mutations and tailored to their downstream signalling programmes or distinct vulnerabilities. Citation Format: Will McDaid. Decoding the codons: Uncovering KRAS mutant isoform-specific vulnerabilities in non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr A011.