In Vivo Functional Platform Targeting Patient- Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer

Current treatment regimens for pancreatic ductal adenocarcinoma (PDAC) yield poor 5-year survival, emphasizing the critical need to identify new druggable targets essential for PDAC maintenance. We developed an unbiased, in vivo target discovery approach to interrogate tumor-initiating cell (TIC) vulnerabilities in low- passage, patient-derived PDAC xenografts or genetically engineered mouse model-derived allografts. Focusing on epigenetic regulators, we identified WDR5, a core member of the COMPASS histone H3 Lys4 (H3K4) MLL (1- 4) methyltransferase complex, as a top tumor maintenance hit required across multiple human and mouse tumors. Mechanistically, WDR5 functions to sustain proper execution of DNA replication in PDAC cells, as previously suggested by replication stress studies involving MLL1, a critical ATR substrate, and c-Myc, also found to interact with WDR5. We indeed demonstrate that interaction with c-Myc is critical for this function. By showing that ATR inhibition mimicked the effects of WDR5 suppression, these data provide rationale to test ATR inhibitors currently in development for activity in this disease as well as prospecting the opportunity to discover novel WDR5 inhibitors.