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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma
Nature medicine, v 23(11), pp 1342-1351
Nov 2017
PMID: 29035366
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 [
F]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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Details
- Title
- Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma
- Creators
- Wilson X Mai - Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, USALaura Gosa - Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, USAVeerle W Daniels - Dana-Farber Cancer InstituteLisa Ta - Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, USAJonathan E Tsang - Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, USABrian Higgins - Pharma Research and Early Development, Roche Innovation Center, New York, USAW Blake Gilmore - Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, USANicholas A Bayley - Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, USAMitra Dehghan Harati - University of California, Los AngelesJason T Lee - Jonsson Comprehensive Cancer Center, David Geffen UCLA School of Medicine, Los Angeles, USAWilliam H Yong - Jonsson Comprehensive Cancer Center, David Geffen UCLA School of Medicine, Los Angeles, USAHarley I Kornblum - Jonsson Comprehensive Cancer Center, David Geffen UCLA School of Medicine, Los Angeles, USASteven J Bensinger - Jonsson Comprehensive Cancer Center, David Geffen UCLA School of Medicine, Los Angeles, USAPaul S Mischel - University of California San DiegoP Nagesh Rao - University of California, Los AngelesPeter M Clark - Jonsson Comprehensive Cancer Center, David Geffen UCLA School of Medicine, Los Angeles, USATimothy F Cloughesy - Jonsson Comprehensive Cancer Center, David Geffen UCLA School of Medicine, Los Angeles, USAAnthony Letai - Dana-Farber Cancer InstituteDavid A Nathanson - Jonsson Comprehensive Cancer Center, David Geffen UCLA School of Medicine, Los Angeles, USA
- Publication Details
- Nature medicine, v 23(11), pp 1342-1351
- Publisher
- Springer Nature
- Grant note
- R01 CA205967 / NCI NIH HHS R56 NS052563 / NINDS NIH HHS P50 CA211015 / NCI NIH HHS R01 CA213133 / NCI NIH HHS R01 NS052563 / NINDS NIH HHS U54 CA199090 / NCI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems; Drexel University
- Web of Science ID
- WOS:000414548300016
- Scopus ID
- 2-s2.0-85033238328
- Other Identifier
- 991019356344704721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology
- Medicine, Research & Experimental