Abstract B063: Exploring combination therapies to overcome RAS inhibitor resistance in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, due in large part to limited therapeutic options and the rapid emergence of treatment resistance. Despite the clinical success of recently developed RAS inhibitors (RASi) resistance to these agents , both mutant-specific and pan-RAS, emerges rapidly, limiting their long-term efficacy. Here, we generated RASi-resistant in vitro and in vivo models of murine and human PDAC. Resistance mechanisms were characterized in vitro using RNA sequencing and phospho-proteomics, and in vivo using spatial transcriptomics. Across these models, we identified convergent mechanisms of resistance, including shared features between mutant-specific and pan-RAS inhibitor-resistant models. Notably, combination strategies that are effective in treatment-naïve models lose efficacy once RASi resistance has emerged. Together, these findings inform the development of more effective combination strategies for PDAC by defining resistance mechanisms and revealing therapeutic vulnerabilities, with potential implications for translational efforts in a disease with significant unmet clinical need.