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

  • Author(s): Mai, Wilson X;
  • Gosa, Laura;
  • Daniels, Veerle W;
  • Ta, Lisa;
  • Tsang, Jonathan E;
  • Higgins, Brian;
  • Gilmore, W Blake;
  • Bayley, Nicholas A;
  • Harati, Mitra Dehghan;
  • Lee, Jason T;
  • Yong, William H;
  • Kornblum, Harley I;
  • Bensinger, Steven J;
  • Mischel, Paul S;
  • Rao, P Nagesh;
  • Clark, Peter M;
  • Cloughesy, Timothy F;
  • Letai, Anthony;
  • Nathanson, David A
  • et al.

Published Web Location

https://doi.org/10.1038/nm.4418
Abstract

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies.

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