Abstract IA006: Genetic co-gain in MYC and KRAS drives resistance to targeting KRAS signaling in pancreatic ductal adenocarcinoma

Abstract

Low-dose MYC copy number gain (minor gain), distinct from high-level amplification, occurs in ∼40% of pancreatic ductal adenocarcinomas (PDAC). While MYC high-level amplification is known to be a poor prognostic factor, the role of low-dose MYC gain is poorly understood. Here we demonstrate in multiple large datasets that MYC gain frequently co-occurs with KRAS gain, creating a feed-forward signal amplification accompanied by 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 critical downstream effector of KRAS signaling. Tumors from four of 14 patients showed Ki-67/CA19-9-based biomarker response (BR). Non-BR tumors were enriched for KRAS G12D /MYC co-gains. A transcriptomic signature predictive for BR tumors was inversely correlated with KRAS/MYC co-gain, especially with G12D variant, in large PDAC datasets and predictive for KRAS inhibitor response in genetic mouse models and patient-derived models. BR tumors had higher spatial proximity of CD8+ T, CD4+ T helper and antigen presentation cells, and increased CD8+ T cell infiltration. Finally, co-targeting KRAS and MYC with new, clinically relevant inhibitors was synergistic in KRAS G12D /MYC co-gain PDAC. Together, this study provides insight into KRAS-MYC cooperation in aggressive PDAC biology and in KRAS inhibitor resistance, providing critical new evidence of the dominant role targeting MYC should play in the next generation treatment landscape for this deadly disease to improve patient outcomes.