Abstract 3905: Epigenetic primming reveals the central role of epigenetic state in the anti-tumor activity of vitamin D in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, which is largely due to the intrinsic resistance to a broad spectrum of therapies. Vitamin D (VD) has been extensively studied as a potential preventive or therapeutic agent for PDAC treatment. Although accumulating evidence supports that VD has beneficial effects on PDAC treatment, controversies still exist. The major reason for this inconsistency is that VD resistance widely occurs in PDAC. However, the underlying mechanism by which the VD resistance occurs remains largely unknown. Here, we report that epigenetic primming by glyceryl triacetate (GTA) and 5-azacytidine (5-Aza) overcomes VD resistance in PDAC. Mechanistically, increasing global H3K27 acetylation with GTA and reducing global DNA methylation with 5-Aza not only elevate the VDR expression but also reprogram the VD responsive genes. Consistently, combination treatment with VD analogue calcipotriol (CPT) and epigenetic primming overcomes the VD resistance to inhibit cell proliferation and migration through activating genes involved in negative regulation of cell proliferation and cell migration, while CPT treatment alone has the opposite effects. Intriguingly, further studies in mouse PDAC cells suggest that VDR expression does not always corelate with VD responsiveness. Using the gain and loss of function experiments, we demonstrate that VDR is necessary but not sufficient to trigger the anti-tumor activity of VD, highlighting that epigenetic state is the key determinant of VD responsiveness in PDAC. Collectively, these data reveal a previously undefined mechanism for VD resistance in PDAC and has the potential to guide VD clinical trials in the future. Citation Format: Bo He, Lauren Stoffel, Clifford Jiajun He, Albert Mao Li, Haowen Jiang, Kumsun Cho, Brittany M. Flowers, Sofia Ferreira, Laura D. Attardi, Jiangbin Ye. Epigenetic primming reveals the central role of epigenetic state in the anti-tumor activity of vitamin D in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3905.