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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We thank H. Herschman, M. Teitell, and T. Graeber for their critical review of the manuscript. This work was funded by National Institutes of Health (NIH)/National Cancer Institute (NCI) R01 CA 213133 (D.A.N.), NIH/NCI UCLA SPORE in Brain Cancer P50 CA 211015 (D.A.N., T.F.C., S.J.B., H.I.K., and W.H.Y.), Nanosystems Biology Cancer Center U54 CA 199090 (D.A.N., T.F.C., and J.T.L.), a Jonsson Comprehensive Cancer Center Foundation/Seed Grant (D.A.N.), the Uncle Kory Foundation (D.A.N. and T.F.C.), the B Hasso Family Foundation (D.A.N. and T.F.C.), the Spiegelman Family Foundation in Memory of Barry Spiegelman (D.A.N. and T.F.C.), the Art of the Brain (T.F.C.), the Ziering Family Foundation (T.F.C. and P.S.M.), the National Brain Tumor Society (T.F.C. and P.S.M.), and the Ben And Catherine Ivy Foundation (T.F.C. and P.S.M.). A.L. and V.W.D. were supported by the Ludwig Institute for Cancer Research and NIH grant R01 CA 205967. H.I.K. was supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and NIH grant NS 052563. W.X.M. was supported by National Science Foundation (NSF) Graduate Research Fellowship Program (GRFP) DGE-114087. We thank L. Abrey, J. Garcia, G. Nichols, S. Middleton, and L. Chen (all at Roche Pharmaceuticals) for their medical and scientific advice regarding idasanutlin; G. Coppola (UCLA) and Y. Qin (UCLA) for assistance in analyzing exome-sequencing data; K. Faull (UCLA) for help with mass spectrometry; L. Baufeld (UCLA) for technical assistance; J. Heath (Caltech) and M. Phelps (UCLA) for helpful discussions; and W. Fromer (Stanford), S. Korsmeyer (Dana-Farber Cancer Institute), R. Agami (The Netherlands Cancer Institute), and G. Lahav (Harvard) for reagents.

Author information


  1. Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, California, USA.

    • Wilson X Mai
    • , Laura Gosa
    • , Lisa Ta
    • , Jonathan E Tsang
    • , W Blake Gilmore
    • , Nicholas A Bayley
    • , Jason T Lee
    • , Harley I Kornblum
    • , Peter M Clark
    •  & David A Nathanson
  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Veerle W Daniels
    •  & Anthony Letai
  3. Pharma Research and Early Development, Roche Innovation Center, New York, New York, USA.

    • Brian Higgins
  4. Department of Pathology, David Geffen UCLA School of Medicine, Los Angeles, California, USA.

    • Mitra Dehghan Harati
    • , William H Yong
    •  & P Nagesh Rao
  5. Jonsson Comprehensive Cancer Center, David Geffen UCLA School of Medicine, Los Angeles, California, USA.

    • Jason T Lee
    • , William H Yong
    • , Harley I Kornblum
    • , Steven J Bensinger
    • , Peter M Clark
    • , Timothy F Cloughesy
    •  & David A Nathanson
  6. Department of Microbiology, Immunology, and Molecular Genetics, David Geffen UCLA School of Medicine, Los Angeles, California, USA.

    • Steven J Bensinger
  7. Ludwig Institute for Cancer Research, University of California San Diego, San Diego, California, USA.

    • Paul S Mischel
  8. Department of Neurology, David Geffen UCLA School of Medicine, Los Angeles, California, USA.

    • Timothy F Cloughesy
  9. Ahmanson Translational Imaging Division, David Geffen UCLA School of Medicine, Los Angeles, California, USA.

    • David A Nathanson


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W.X.M., T.F.C., and D.A.N. conceived the study. W.X.M., L.G., V.W.D., L.T., J.E.T., B.H., W.B.G., N.A.B., M.D.H., J.T.L., W.H.Y., P.N.R., A.L., and D.A.N. designed and/or conducted the experiments and analyzed data. B.H., H.I.K., S.J.B., P.S.M., P.M.C. and A.L. provided reagents, cell lines, and critical input. W.X.M. and D.A.N. wrote the original manuscript. All authors read and edited the manuscript.

Competing interests

B.H. is an employee of Roche. T.F.C. has received consulting fees from Roche.

Corresponding author

Correspondence to David A Nathanson.

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