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Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma
- 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.4418Abstract
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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