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Abstract ID 93056 Poster Board 047 Pancreatic cancer being the deadliest among solid tumors, holds multiple challenges with an overall 5-year survival rate of only 12%. Aggressive invasive and metastatic properties of this cancer along with delayed detection and drug resistance necessitate new treatments. Unchecked cell proliferation due to spontaneous cell cycle activity along with altered epigenetic signatures leads to uncontrolled cancer cell growth and proliferation. Our previous results targeting histone deacetylases (HDACs) with Panobinostat (Pan) and cyclin-dependent kinases 4/6 (CDK4/6) with Abemaciclib (Abe), and their combination significantly affected pancreatic cancer cell growth and proliferation with a significant decrease in c-Myc protein levels. Our study unraveled apoptosis as a mode of cell death in a combination treatment group with significantly higher cleaved caspase-3 and low survivin protein levels along with higher caspase-3 activity compared to the control. We also showed both drugs individually and in combination altered target protein levels including epigenetic marker acetylated H3 (Ac-H3) and phosphorylated Rb (pRb) levels leading to cancer cell death. Cellular epigenetic alterations and changes in cell cycle circuit have been previously shown to rewire tumor cell metabolism potentiating the growth of pancreatic cancer. Deregulated cellular metabolism, one of the hallmarks of pancreatic cancer can be targeted using drugs acting on HDACs and CDK4/6 playing a role in epigenetic and cell cycle regulation. Therefore, we aimed to study the pharmacological effects of Abe, Pan, and combination treatment on glucose metabolism in pancreatic cancer cells. We investigated the effects of Abe, Pan, and the combination on modulation of transcriptional levels of glucose metabolizing enzymes by qPCR, protein levels by western blotting, and measuring their enzymatic activity. We also performed extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) analysis to evaluate the effect on cellular metabolism pathways upon Abe, Pan, and combination treatments in pancreatic cancer cells. Our results suggest that a combination of Abe and Pan targeting cell cycle and epigenetics modulates cancer cell metabolism causing drastic effects on pancreatic cancer cell growth. Further studies will elucidate the molecular mechanisms of the combination and will aid in testing the therapeutic potential of the novel combination. The College of Pharmacy and Health Sciences at St. John's University in New York provided funding for this study together with support from the National Institute of General Medical Sciences (Award Number R16GM145557).
Bhutkar et al. (Mon,) studied this question.