Abstract 1815: Targeting the serine metabolism-NRF2 axis to overcome radiation resistance in pancreatic cancer

Abstract Pancreatic ductal adenocarcinomas (PDAC) have very poor prognosis largely due to extreme resistance to existing therapies, including radiation therapy (RT). Metabolic reprogramming has been shown to promote therapy resistance in PDAC, but little in known in the context of RT. Here, we present findings of a critical intersection between serine metabolism and antioxidant defenses following RT of PDAC that place serine metabolism in a radioprotective role. We find that this is enabled, in part, by the upregulation of the NRF2 (nuclear factor (erythroid-derived 2)-like 2) pathway following RT, beyond basal, mKRAS-induced levels. Our discovery is in line with the role that the serine metabolism coupled with one-carbon metabolism (1CM) plays in generating antioxidants for offsetting oxidative damage, as well as generating nucleotide precursors for DNA repair. Our TCGA analysis on patient PDAC shows a significant correlation between tumor NRF2 expression and SLC1A5 serine transporter, PSPH (the last enzyme in serine synthesis) and NADPH-producing enzymes of 1CM. Moreover, co-overexpression of PHGDH and NRF2 correlates with poorer overall survival, underscoring the intersection of serine metabolism and NRF2-regulated antioxidant responses in human PDACs. In pre-clinical models we show that RT enhances PDAC cellular glucose consumption in excess of anabolic basal levels, and this is accompanied by increased gene expression levels of enzymes that drive the de novo serine biosynthesis pathway (SBP), a branch of glycolysis. PDAC radiosensitization can be achieved by interfering with serine metabolism, be it through inhibiting the first SBP enzyme, phosphoglycerate dehydrogenase, or by removing exogenous serine. The radiation-induced antioxidant pathway involving NRF2 is also implicated in metabolic PDAC reprogramming in part by promoting upregulation of glucose consumption following RT and driving flux of glucose carbons into the SBP. In keeping with this, PDAC radiosensitization can also be achieved by inhibiting the NRF2 pathway (in vitro and in vivo). Our findings suggest that NRF2-serine-metabolism axis generates a synchronized metabolic response that protects PDAC from lethality in the aftermath of RT and constitutes a promising and novel radiotherapeutic target. Citation Format: Prince Kumar, Hüseyin Ayhan, Lobna Abdulrahman, Justine Bailleul, Jonathan Ng, Erina Vlashi. Targeting the serine metabolism-NRF2 axis to overcome radiation resistance 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 1815.