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

Copy number alterations of <i>KRAS,</i> mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), and <i>MYC</i> occur in 30-40% of PDAC. Here we demonstrate that <i>KRAS</i> and <i>MYC</i> 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 inhibition, 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 <i>KRAS</i> / <i>MYC</i> co-gain and <i>KRAS ^G12D</i> variant. A transcriptomic signature of BR tumors was inversely correlated with <i>KRAS ^G12D</i> / <i>MYC</i> 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 <i>KRAS ^G12D</i> / <i>MYC</i> 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.