Abstract 1092: Targeting one-carbon metabolism radiosensitizes pancreatic ductal adenocarcinoma cells (PDAC)

One of the most challenging aspects of PDAC is intense therapeutic resistance towards radiotherapy. Cellular signaling pathways are tightly regulated to protect and withstand constant DNA-damaging insults. Similarly, pancreatic cancer cells are known to activate important metabolic events in the advent of cellular stress. Fuel sources obtained via the high metabolic flexibility of PDAC cells confer on them enhanced survival and the ability to escape therapy-induced cell death. To this end, we aim to dissect the role of altered metabolic reprogramming in radioresistant PDAC cells. Investigation of systemic metabolic changes post-radiation of 8Gy in in vitro systems revealed reduced total NAD/NADH ratio and hinted at the increased dependency of PDAC cells on the one-carbon metabolic pathway. Using combinatorial stable-isotope tracing techniques, we confirmed the role of methylene tetrahydrofolate dehydrogenase (MTHFD1/2) enzymes as key regulators in maintaining total NAD/NADH ratio in irradiated cells. Moreover, inhibition of the one-carbon metabolic pathway hindered the ability of PDAC cells to resolve radiation-induced DNA damage. In summary, we propose that PDAC cells modulate the flux of MTHFD1/2 enzymes to reprogram their metabolic state and generate intermediates for DNA repair and cell survival, thus establishing MTHFD1/2 enzymes as potential therapeutic targets to tackle radioresistance. Citation Format: Minal Nenwani, Abhinav Achreja, Olamide Animasahun, Itisam Sarangi, Jyotirmoy Roy, Srinadh Choppara, Fulei Wuchu, Miya Paserba, Anjali Mittal, Sergio Quispe, Aradhana Mohan, Meredith Morgan, Theodore S. Lawrence, Deepak Nagrath. Targeting one-carbon metabolism radiosensitizes pancreatic ductal adenocarcinoma cells (PDAC) [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 1092.