Skip to main content
eScholarship
Open Access Publications from the University of California

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.

Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.

Main Content
Current View