Irradiation Reprograms Gbm Metabolism Towards An Antioxidant Profile That Drives Radiation Resistance

The purpose of this study was to investigate the role of the Nrf2 pathway in activating a redox-sensitive, PKM2-operated metabolic switch that boosts antioxidant defense mechanisms, and drives cell survival in irradiated GBM cells. We also determined whether targeting the redox-Nrf2-PKM2-metabolism axis reverses the radioresistant phenotype of GBM tumors for improved outcomes. Human, patient-derived GBM specimen were used in combination with metabolic assays, including targeted glucose metabolomics with 13C-glucose, to determine the effect of radiation on the metabolism of GBM cells. PKM2 small molecule activators, Nrf2 small molecule inhibitors and Crispr/Cas9 targeted deletion of Nrf2 were used to elucidate the role of Nrf2 and PKM2 in driving metabolic reprogramming towards anti-oxidant metabolism during radiation. Irradiated GBM cells reprogram their glucose metabolism; increasing glucose uptake and funneling it through the anti-oxidant pentose phosphate pathway (PPP), in an Nrf2 and PKM2-dependent manner. Inhibition of the Nrf2 pathway sensitized GBM cells to ionizing radiation (IR) and this was further enhanced when both Nrf2 and PKM2 were targeted. Furthermore, small molecule activators of PKM2, that can cross the blood brain barrier, sensitize GBM cells to IR in vitro and in vivo with no effect on normal brain cells. Our studies show that GBM cells have remarkable metabolic flexibility that results in irradiated GBM cells reprogramming their metabolism towards anti-oxidant pathways that support cell survival and radiation resistance. Interfering with the Nrf2-PKM2-metabolism axis reverses the disables the radiation-induced metabolic reprogramming in GBM cells, and serves as a therapeutic target in the context of radiation therapy.