Abstract A128: Vitamin B3 derivatives support pancreatic cancer cell survival and chemotherapy resistance

Abstract Background: Nicotinamide adenine dinucleotide (NAD+) is a central metabolic cofactor essential for cell survival and stress response in normal tissues. Its dietary precursors, commonly referred to as vitamin B3 derivatives, including nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN), are marketed as nutraceuticals with potential energy-boosting, cardioprotective, and neuroprotective benefits. Consequently, many cancer patients utilize NAD+ precursors to alleviate chemotherapy-induced toxicity and promote health. however, the impact of NAD+ supplements on the intrinsic biology of tumors and the progression of particularly aggressive cancers like pancreatic ductal adenocarcinoma (PDAC) remains controversial and not fully understood. There are conflicting reports about how NAD+ supplementation affects cancer biology. Some studies suggest that supplementing with NAM or NR enhances chemosensitivity, increases apoptosis, and decreases metastasis in pancreatic, breast, and liver cancers. Additionally, supplementation could boost the anti-cancer immune response, thereby inhibiting the growth of lung and colorectal cancers. cancers. Still, other studies show that vitamin B3 derivatives could increase metastasis and aggressiveness in other cancer types, including breast and cervical cancers. Methods: We evaluated the effects of common vitamin B3 derivatives, NAM, NR, and NMN, on chemotherapy effectiveness in PDAC using both in vitro and in vivo models. Results: PDAC cells increase NAD+ production in response to nutrient limitation and chemotherapeutic stress. Baseline intracellular NAD+ and NAM levels were higher in cancer cells compared to non-cancer cells. Among the compounds tested, NMN showed the strongest protective effect on cancer cells, increasing resistance to oxaliplatin, 5-fluorouracil, and gemcitabine in vitro. Mechanistically, NAD+ precursors enhanced mitochondrial function, reduced oxidative stress, and decreased DNA damage and apoptosis in treated cancer cells, all contributing to chemotherapy resistance. In murine models, both immunocompetent and immunodeficient, supplementation with NAM and NMN similarly provided resistance to standard chemotherapy and supported tumor growth. Conclusions: Our findings highlight a potentially concerning role for NAD+ boosting supplements in the context of an active cancer, especially when used in conjunction with therapy. These data underscore the need for careful evaluation of nutraceutical use in cancer patients, particularly those with PDAC, as vitamin B3 derivatives may inadvertently promote tumor cell survival and compromise treatment efficacy. Citation Format: Faith Nakazzi, Mehrdad Zarei, Jordan M. Winter, Hallie Graor, Peder Lund. Vitamin B3 derivatives support pancreatic cancer cell survival and chemotherapy resistance abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr A128.