Pancreatic ductal adenocarcinoma (PDAC) is a disease with poor prognosis, with an overall survival rate of only 10%. Standard of care involves chemotherapy which improves survival by only a few weeks. Several barriers to therapeutic efficacy impede increasing survival outcome, including intrinsic resistance, owing to presence of therapy-resistant pancreatic cancer stem-like cells (PCSCs). Therefore, developing therapeutics to target molecular networks that maintain PCSC populations is critical. Microarray analysis from our lab previously established that pancreas lineage transcription factor HNF1A and its targets are enriched in CD44+CD24+EPCAM+ human PCSCs and that genetic depletion of HNF1A ablates this population and importantly, diminished tumor growth in primary PDAC xenografts. However, there are no therapeutics to directly target HNF1A. In this project, we propose to indirectly ablate HNF1A and its network by targeting epigenetic readers, bromodomain and extra-terminal domain protein family (BET) that maintain expression of transcription factor networks. We hypothesize that BET inhibitors decrease stemness and tumor growth in a HNF1A-dependent manner. Studies in our lab established that BET inhibitors decrease colony-formation, tumorsphere formation and cell-cycle progression in PDAC cells, that is rescued by overexpressing HNF1A. These results indicate that BET inhibitors decrease stemness and proliferation in pancreatic cancer cells in a HNF1A-dependent manner. These results suggest that BET inhibitors target multiple HNF1A-dependent tumor-promoting programs, such as stemness and tumor growth which could impact utilization of these drugs in clinical settings. The ultimate goal of our project is to provide rationale for the use of BET inhibitors in clinical setting in pancreatic cancer.

Citation Format: Bharani Muppavarapu, Ethan Abel, Melanie Mayberry. Targeting HNF1A-dependent cell proliferation and stemness in PDAC using BET inhibitors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-045.