Abstract B042: Therapeutic options for cancers with oncogenic Ras mutations

Abstract Each year, approximately 3.4 million patients are afflicted with cancer containing a mutation in a Ras gene. Recently developed pan-RasON tri-complex inhibitors such as daraxonrasib can inhibit mutant Ras alleles that are beyond the scope of clinically approved KRAS G12C inhibitors. Daraxonrasib is currently in clinical trials for multiple solid tumors, including non-small cell lung cancer and pancreatic ductal adenocarcinoma. Inhibiting previously untargetable alleles of Ras oncogenes can vastly expand the treatable population, and understanding mechanisms of drug resistance can provide opportunities for rational combination therapies that will improve outcomes, yet relationships between mutant genotypes and mechanisms of inhibitor resistance remain unclear. We employ multiple Ras isogenic systems to study how mutant Ras alleles affect drug-response phenotypes including proliferation, drug tolerance, cell migration, macropinocytosis, metabolism, signaling, and transcriptional changes in drug-tolerant persister cells. We identified multiple genotype-phenotype differences, particularly in KRAS G12R models. Mutant KRAS drove overexpression of glycolytic enzymes and immunosuppressive signals. In spheroid models, therapeutic combinations of daraxonrasib with blockade of glycolysis and stimulated CD8+ T-cell co-coculture significantly decreased proliferation and enhanced apoptosis. Ras inhibition and metabolic blockade drove CD8+ T-cells toward effector memory-like differentiation states. These results highlight genotype-dependent effects and combinatorial strategies that can improve our ability to understand treatment strategies for cancers driven by mutant Ras. Citation Format: Leonard J. Ash, Ottavia Busia-Bourdain, Elesha McGrath, Akriti Khanal, Olimpia P. Gavaudan, Amani Nation, Dennis Lam, Brandon Ely, Dustyne J. Steele, Ahava Collado, Jillian M. Silva, Jacqueline Galeas, Weigang Qiu, Frank McCormick, Andrew L. Wolfe. Therapeutic options for cancers with oncogenic Ras mutations [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 B042.