Abstract 2326: Nicotinamide adenine dinucleotide precursors delay pancreatic cancer initiation and progression by promoting DNA repair and improving mitochondrial function

Abstract Background: Pancreatic cancer (PC) is the third leading cause of cancer-related death in the United States, with a dismal 5-year survival rate of just 13%. Because PC has no screening biomarkers and is aggressive and resistant to most chemotherapy, focus should be put on discovering PC preventative alternatives. Cancer progression is driven primarily by increased cellular reactive oxygen species and mitochondrial dysfunction(definition) in cells, which promote somatic DNA mutations and, eventually, cancer initiation. Nicotinamide adenine dinucleotide (NAD+) precursors have shown promise in maintaining redox balance, cellular signaling, DNA repair, and mitochondrial function in aging-related non-malignant conditions. We investigated the impact of NAD+ supplementation on stressed pancreatic ductal epithelial cells and PC progression in an autochthonous pancreatic cancer mouse model. Methods: We evaluated three NAD+ salvage pathway precursors Nicotinamide mononucleotide (NMN), Nicotinamide (NAM), and Nicotinamide riboside (NR) on non-transformed pancreatic ductal epithelial cell lines (HPDE, HPNE) under various stressors: phenformin (to simulate mitochondrial dysfunction), oxaliplatin (to induce DNA damage), and hydrogen peroxide (to induce oxidative stress). We assessed cell viability, mitochondrial function, reactive oxygen species (ROS) levels, DNA repair, and mutation rates. Additionally, we treated p48Cre/+-LSL-KRASG12D/+ mice with either vehicle or NAM (400mg/kg for 6 months starting at 8 weeks), sacrificed the mice, and obtained pancreases to asses pancreatic intraepithelial neoplasm (PanIN) progression, DNA damage, and immunological markers. Results: NAM-treated mice showed predominantly focal low-grade PanINs, while vehicle-treated mice developed primarily diffuse high-grade PanINs, indicating delayed cancer progression. There were increased H2AX foci, increased inflammation markers (Cox-2 and pSTAT3), and increased lipid peroxidation in vehicle-treated mice’s pancreases compared to those treated with NAM. In vitro, NMN enhanced cell survival under stress due to improved oxygen consumption rate, increased ATP production, and reduced cellular reactive oxygen species levels; NMN treatment also promoted Nrf-2 nuclear translocation and increased expression of superoxide dismutase and glutathione. NMN supplementation also enhanced DNA repair through increased PARylation. These effects resulted in reduced mutation rates in NMN-treated cells. Conclusions: NMN protects pancreatic epithelial cells from stress by enhancing DNA repair, improving mitochondrial function, and maintaining redox homeostasis. These mechanisms likely contribute to the delayed cancer progression observed in NAM-treated mice, suggesting that NAD+ precursors are promising candidates for pancreatic cancer prevention. Citation Format: Faith Nakazzi, Mehrdad Zarei, Omid Hajihassani, Hallie J. Graor, Priyashree Sunita, Goutam Dey, Akram S. Shalaby, Jordan M. Winter. Nicotinamide adenine dinucleotide precursors delay pancreatic cancer initiation and progression by promoting DNA repair and improving mitochondrial function [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 2326.