Abstract B092: Investigating combination therapies to overcome RAS inhibitor resistance in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal malignancies, largely due to limited therapeutic options and the rapid development of treatment resistance. Recent progress in the development of RAS targeting agents, including mutant-specific and pan-RAS inhibitors, has expanded potential treatment strategies for tumors harboring oncogenic KRAS mutations. However, clinical and preclinical evidence indicates that resistance to these agents emerges rapidly, limiting their long-term efficacy. This study aims to investigate the mechanisms underlying resistance to RAS inhibitors and to identify rational combination strategies that enhance therapeutic durability in PDA. Using advanced organoid and in vivo models, we are characterizing resistance to clinically relevant RAS inhibitors and evaluating the therapeutic potential of combining RAS inhibition with other targeted agents. We will also examine the influence of treatment timing, drug synergy, and tumor microenvironmental factors, including immune interactions, on treatment response. Ultimately, this research seeks to inform the development of more effective combination strategies for PDA by elucidating resistance mechanisms and identifying therapeutic vulnerabilities. Insights from this work may support future translational efforts in a disease with pressing unmet clinical needs. Citation Format: Vasiliki Pantazopoulou, Casie Kubota, Satoshi Ogawa, Kassidy Curtis, Araceli Herrera Morales, Dannielle Engle. Investigating combination therapies to overcome RAS inhibitor resistance in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B092.