Abstract 1184: Studying circadian disruption in pancreatic ductal adenocarcinoma

Our long-term goal is to understand the role of the circadian clock in pancreatic ductal adenocarcinoma (PDAC) to shift the therapeutic landscape for patients with this lethal cancer. The circadian clock is a highly conserved molecular feedback loop where cell-autonomous cycling of the core clock genes (e.g. BMAL1, PER1, PER2) controls the expression of numerous other genes to regulate functions such as apoptosis, proliferation, metabolism and immune function. Research has shown that malignant tumors, including pancreatic ductal adenocarcinoma, can dampen the circadian clock to accelerate cancer progression making it an attractive target in cancer therapy. Existing evidence shows that BMAL1 suppression in PDAC leads to a more aggressive phenotype and worse prognosis. To investigate the role of the clock disruption in PDAC, we created and validated a Kras- and p53-mutant PDAC cell line with a disrupted clock, by knocking out the core circadian clock gene BMAL1 which is essential for clock function. We performed syngeneic heterotopic tumor implant studies and found that clock-disrupted PDAC demonstrated substantially increased tumor growth in vivo compared to PDAC with an intact clock. Secondly, we developed a novel patient-derived xenograft approach to discern circadian parameters and identify which patient cancers harbor an intact versus suppressed clock. RNA sequencing of the tumors over 24 hours revealed a striking suppression of BMAL1 expression in patients who presented with a more aggressive disease. Thirdly, to assess the possibility that dysregulation of BMAL1 in PDAC drives a more aggressive phenotype through rewiring of the tumor metabolism, we assessed oxygen consumption and glycolytic flux in our KPC-WT and KPC-BKO cells and found marked differences in mitochondrial respiration and glycolytic function. Overall, targeting the circadian clock in cancer offers a promising avenue for improving patient prognosis by enabling the development of novel therapies. Citation Format: Ksenija Korac, Sean Ronnekleiv-Kelly. Studying circadian disruption in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1184.