Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for novel therapeutic strategies in cancer. Here we show that acute inhibition of EGFR-driven glucose metabolism induces minimal cell death, yet lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that, following attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, pharmacological stabilization of p53 with the brain-penetrant small molecule, Idasanutlin, in combination with targeting EGFR-driven glucose metabolism promoted synthetic lethality in orthotopic xenograft models. Notably, neither inhibition of EGFR signaling, nor genetic analysis of EGFR, was sufficient to predict sensitivity to this new therapeutic combination. Conversely, rapid changes in (18)F-fluorodeoxyglucose ((18)F-FDG) uptake using non-invasive positron emission tomography was an effective predictive biomarker of response in vivo. Together, these studies identify a critical link between oncogene signaling, glucose metabolism, and cytoplasmic p53, which could be exploited for combination therapy in GBM and potentially, other malignancies.