Abstract B030: A window trial in metastatic pancreatic ductal adenocarcinoma reveals resistance mechanisms to targeting the KRAS-MEK pathway

Abstract Copy number alterations of KRAS, mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), and MYC occur in 30-40% of PDAC. Here we demonstrate that KRAS and MYC are frequently co-gained and accompanied with worse prognosis in PDAC. In a Window-of-Opportunity clinical trial for metastatic PDAC, serial biopsies and deep multi-omics analyses were utilized to explore resistance mechanisms to MEK inhibitior cobimetinib, as a surrogate for KRAS inhibition. Tumors from four of 14 patients showed Ki-67/CA19.9-based biomarker response (BR). Non-BR tumors were enriched for KRAS/MYC co-gain and KRAS G12D variant. A transcriptomic signature of BR tumors was inversely correlated with KRAS G12D /MYC co-gain in a large PDAC dataset and predictive for KRAS inhibitor response in multiple models. Finally, co-targeting KRAS and MYC was synergistic in KRAS G12D /MYC co-gain PDAC. Together, this study provides insight into KRAS inhibitor resistance and supports MYC as an important target to improve patient outcomes in this deadly disease. Citation Format: Motoyuki Tsuda, Dove Keith, Colin J. Daniel, Carl Pelz, Katie E. Blise, Laura Soucek, Lisa M. Coussens, Jonathan R. Brody, Charles D. Lopez, Gordon B. Mills, Rosalie C. Sears. A window trial in metastatic pancreatic ductal adenocarcinoma reveals resistance mechanisms to targeting the KRAS-MEK pathway [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 B030.