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

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

Author information

1
Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, California, USA.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
3
Pharma Research and Early Development, Roche Innovation Center, New York, New York, USA.
4
Department of Pathology, David Geffen UCLA School of Medicine, Los Angeles, California, USA.
5
Jonsson Comprehensive Cancer Center, David Geffen UCLA School of Medicine, Los Angeles, California, USA.
6
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen UCLA School of Medicine, Los Angeles, California, USA.
7
Ludwig Institute for Cancer Research, University of California San Diego, San Diego, California, USA.
8
Department of Neurology, David Geffen UCLA School of Medicine, Los Angeles, California, USA.
9
Ahmanson Translational Imaging Division, David Geffen UCLA School of Medicine, Los Angeles, California, USA.

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.

PMID:
29035366
PMCID:
PMC5683421
DOI:
10.1038/nm.4418
[Indexed for MEDLINE]
Free PMC Article

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