Abstract 6769: Modeling of acquired resistance to the multi-RAS inhibitor RMC6236 in KRAS mutant pancreatic ductal adenocarcinoma

Abstract Mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) are among the most prevalent oncogenic events in human cancers, with KRAS G12D being the dominant driver in pancreatic ductal adenocarcinoma (PDAC). While covalent KRAS G12C inhibitors have demonstrated clinical efficacy, the absence of effective therapies for non-G12C variants underscores the need for broader KRAS-directed approaches. The recent development of RMC6236, a RAS-MULTI(ON) inhibitor, has shown promising activity in KRAS G12D-driven PDAC, emphasizing the importance of understanding mechanisms underlying acquired resistance to this class of agents. To enable investigation of KRAS resistance pathways, we have established a panel of KRAS G12D PDAC cell models with acquired resistance to RMC6236 using a combination of CRISPR-Cas9-mediated genome editing and advanced engineering techniques. In addition, KRAS-mutant tumor models with engineered inhibitor resistance have been established to support pharmacology and efficacy evaluations. Genomic and functional characterization of these models reveal diverse mechanisms contributing to resistance, including secondary KRAS mutations (Y64C/D/H), BRAF alterations, and MAP2K1 variants, each associated with reactivation of the RAF-MEK-ERK signaling cascade. Beyond genetic adaptations, transcriptional profiling and phenotypic assays indicate the involvement of non-genetic mechanisms such as pathway rewiring and adaptive signaling plasticity. These resistance models provide a controlled experimental framework for dissecting the molecular determinants of multi-RAS inhibitor resistance, and enable comparative evaluation of resistance mechanisms across KRAS alleles, supporting rational development of combination strategies to sustain KRAS pathway inhibition. Collectively, these studies advance our understanding of adaptive resistance to next-generation KRAS inhibitors and inform translational strategies for KRAS G12D-mutant pancreatic cancer. Citation Format: Di Zhan, Jiajia Mei, Jing Yang, Ya Xu, Qikuan Chen, Yuzhou Xu, Yun Zhang, Yinfei Yin. Modeling of acquired resistance to the multi-RAS inhibitor RMC6236 in KRAS mutant pancreatic ductal adenocarcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6769.