Abstract 1696: Combination therapy of cell cycle inhibitor and HDAC inhibitor induces metabolic alterations in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC), characterized by several multigene mutations, is one of the lethal solid cancers accounting for several drug treatment challenges. NCI statistics show that the overall 5-year survival rate of PDAC remains at 12.8%. The tumor aggressiveness and invasive-metastatic potential of the cancer, along with drug resistance issues, demand the development of novel and effective multi-drug therapies. Our initial results show that combination therapy of a cell cycle inhibitor Abemaciclib (Abe), and histone deacetylase inhibitor Panobinostat (Pan) effectively decreases pancreatic cancer cell proliferation and growth and causes apoptotic cell death. Cell cycle and epigenetic changes drive tumor progression by rewiring metabolic signaling pathways of pancreatic cancer cells. Therefore, we hypothesized that co-treatment of pancreatic cancer with Abe and Pan modulates cancer cell metabolism, developing energy imbalance leading to cell death. Our Seahorse metabolic experiments depicted a reduced oxygen consumption rate upon combination treatment in pancreatic cancer cells with upregulation of extracellular acidification rate. We also performed metabolomic profiling upon combination treatment in pancreatic cancer cells, revealing alterations in the levels of metabolites involved in carbohydrate, lipid, and amino acid metabolism in the combination treatment group compared to control pancreatic cells. We also observed a moderate increase in mitochondrial membrane potential upon combination treatment, suggesting altered mitochondrial metabolic signatures compared to control and individual drugs along with combination treatments. These results suggest that mitochondrial dysfunction may underlie the Abe and Pan combination treatment, impairing metabolic homeostasis and energy balance. Our future studies include deciphering the in-depth mechanism of alterations in mitochondrial dynamics and metabolic signaling pathways upon combining cell cycle and HDAC inhibitor treatment in pancreatic cancer cells by performing transcriptomic profiling on PDAC cells and in vivo xenograft studies. This study is funded by the College of Pharmacy and Health Sciences at St. John’s University, New York, and is also supported by the National Institute of General Medical Sciences (Award Number R16GM145557). Citation Format: Shraddha P. Bhutkar, Anjali Yadav, Vikas V. Dukhande. Combination therapy of cell cycle inhibitor and HDAC inhibitor induces metabolic alterations in pancreatic cancer [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 1696.