The current 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is ~8%. The dismal prognosis in PDAC reflects in part an exceptional level of resistance to available therapies. Approximately half of PDAC patients present with localized tumors amenable to local therapies, though only a minority are candidates for potentially curative surgery due to unresectable disease, which leaves radiation therapy (RT) as the only other option. The clinical reality is that two thirds of all PDAC patients succumb to local disease burden regardless of clinical stage at diagnosis. Therefore, improving the effectiveness of PDAC RT has the potential to transform overall outcomes for this lethal disease. More than a century after its discovery, RT remains a powerful therapeutic agent against many cancers, but has largely failed to offer much benefit to PDAC patients according to randomized, controlled clinical trials. The biologic reasons for such exceptional radiation resistance remain obscure. However, studies show that activating KRAS mutations in PDAC drive a NRF2-controlled antioxidant program that endows tumor cells with a reduced intracellular environment and lower levels of reactive oxygen species (ROS). Such persistent NRF2 pathway activation would poise PDAC cells to resist oxidative stress induced by radiation and in all likelihood limits the effectiveness of RT in the clinic. Supporting this hypothesis, our study shows that radiation activates the NRF2 pathway, as well as autophagy, and inhibition of either pathway sensitizes PDAC cells to radiation. Moreover, the radiosensitizing effect is enhanced when both the NRF2 and autophagy pathways are inhibited and, perhaps most importantly, NRF2 or autophagy inhibition radiosensitizes the notoriously therapy-resistant PDAC cancer stem cells. Supporting a role for NRF2 in protecting PDAC cells from radiation-induced oxidative stress, irradiated PDAC cells with depleted NRF2 have elevated ROS levels compared to NRF2-wt controls. Interestingly, irradiated PDAC cells reprogram their glucose and glutamine metabolism in an NRF2-dependent manner and seem to reroute glucose through the antioxidant pentose phosphate pathway (PPP), likely for the generation of reducing equivalents in the form of NADPH. This suggests that NRF2 drives metabolic rewiring in irradiated PDAC cells in favor of cellular antioxidant responses. Taken together, our data strongly suggest that NRF2 plays a pivotal role in promoting radiation resistance of KRAS-mutated PDAC tumors by driving powerful antioxidant responses through metabolic reprogramming and cytoprotective autophagy. If this is correct, the NRF2-autophagy-metabolism axis may be targeted therapeutically to reverse the chemo/radioresistant phenotype of PDAC.

Citation Format: Justine Bailleul, Taha Yazal, David Sung, Daisy Palomera, Anahita Sehgal, Amy Dao, Erina Vlashi. NRF2 drives metabolic reprogramming in irradiated pancreatic cancer cells and promotes radioresistance [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C59.