Cytoplasmic p53 Couples Oncogene-Driven Glucose Metabolism to Apoptosis and Is a Therapeutic Target in Glioblastoma

Nat Med. 2017 Nov;23(11):1342-1351. doi: 10.1038/nm.4418. Epub 2017 Oct 9.

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.

MeSH terms

  • Animals
  • Apoptosis*
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology
  • Cytoplasm / metabolism*
  • ErbB Receptors / metabolism
  • Female
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology
  • Glucose / metabolism*
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • ErbB Receptors
  • Glucose