Abstract PO-020: The NRF2-redox-metabolism axis protects pancreatic cancer cells from radiation toxicity

Abstract

Abstract More than 90% of pancreatic ductal adenocarcinomas (PDAC) are driven by activating KRAS mutations (mKRAS), which promote a remarkable resistance to all non-surgical therapies, including radiation therapy (RT). Unfortunately, mKRAS remains undruggable for the vast majority of PDAC tumors. This necessitates the discovery of downstream targets, which most likely govern the oxidative stress response and promote the acquisition of radiation resistance. Notably, the master orchestrator of oxidative stress response, the transcription factor NRF2, is upregulated by mKRAS and in some models, NRF2 is activated by irradiation (IR). This suggests that IR may amplify the already heightened, mKRAS-driven activation of NRF2 in PDAC. NRF2 targets include genes involved in restoring redox balance, likely promoting survival during RT. However, the involvement of NRF2 in PDAC radioresistance remains unknown. To fill this knowledge gap, we have systematically investigated the role of the NRF2 pathway in regulating radiation response in PDAC tumors. Our studies show that depletion of NRF2 via CRISPR/Cas9 targeted gene deletion (NRF2-ko) results in the accumulation of significantly higher levels of reactive oxygen species in irradiated PDAC cells. Importantly, this correlates with increased radiosensitivity of NRF2-ko cells in vitro, compared to NRF2-wt controls. Interestingly, irradiation of PDAC cells upregulates the expression of metabolic genes that drive the generation of various antioxidant species, in a NRF2-dependent manner. At the metabolite level, IR induces re-routing of glycolytic metabolites towards the antioxidant pentose phosphate pathway and the depletion of NRF2 abrogates these changes. Together, these findings suggest that part of the mechanism via which NRF2 promotes radiation survival of PDAC cells is by reprogramming cellular metabolism to drive a metabolic antioxidant response. Altogether, these findings support a crucial role for the NRF2-redox-metabolism axis in driving RT resistance in PDAC. This further suggests that inhibition of the NRF2 pathway would be followed by a failure to resist IR-induced oxidative stress, and subsequently sensitize mKRAS pancreatic cancer to RT. Citation Format: Justine Bailleul, Taha Yazal, David Sung, Juan Nathaniel, Daisy Palomera, Anahita Sehgal, Rachel Ruan, Erina Vlashi. The NRF2-redox-metabolism axis protects pancreatic cancer cells from radiation toxicity [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-020.