EGFR Signaling Through an Akt-SREBP-1–Dependent, Rapamycin-Resistant Pathway Sensitizes Glioblastomas to Antilipogenic Therapy

Deliang Guo(University of California, Los Angeles), Robert M. Prins(University of California, Los Angeles), Julie Dang(University of California, Los Angeles), Daisuke Kuga(University of California, Los Angeles), Akio Iwanami(University of California, Los Angeles), Horacio Soto(University of California, Los Angeles), Kelly Lin(University of California, Los Angeles), Tiffany Huang(University of California, Los Angeles), David Akhavan(University of California, Los Angeles), M. Benjamin Hock(University of California, Los Angeles), Shaojun Zhu(University of California, Los Angeles), Ava A. Kofman(University of California, Los Angeles), Steve J. Bensinger(University of California, Los Angeles), William H. Yong(University of California, Los Angeles), Harry V. Vinters(University of California, Los Angeles), Steve Horvath(University of California, Los Angeles), Andrew D. Watson(University of California, Los Angeles), John G. Kuhn(The University of Texas at San Antonio Health Science Center), H. Ian Robins(University of Wisconsin–Madison), Minesh P. Mehta(University of Wisconsin–Madison), Patrick Y. Wen(Dana-Farber Cancer Institute), Lisa M. DeAngelis(Memorial Sloan Kettering Cancer Center), Michael D. Prados(University of California, San Francisco), Ingo K. Mellinghoff(Memorial Sloan Kettering Cancer Center), Timothy F. Cloughesy(University of California, Los Angeles), Paul S. Mischel(University of California, Los Angeles)
Science Signaling
December 15, 2009
10.1126/scisignal.2000446
Cited by 344Open Access
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Abstract

Glioblastoma, the most common malignant brain tumor, is among the most lethal and difficult cancers to treat. Although epidermal growth factor receptor (EGFR) mutations are frequent in glioblastoma, their clinical relevance is poorly understood. Studies of tumors from patients treated with the EGFR inhibitor lapatinib revealed that EGFR induces the cleavage and nuclear translocation of the master transcriptional regulator of fatty acid synthesis, sterol regulatory element-binding protein 1 (SREBP-1). This response was mediated by Akt; however, clinical data from rapamycin-treated patients showed that SREBP-1 activation was independent of the mammalian target of rapamycin complex 1, possibly explaining rapamycin's poor efficacy in the treatment of such tumors. Glioblastomas without constitutively active EGFR signaling were resistant to inhibition of fatty acid synthesis, whereas introduction of a constitutively active mutant form of EGFR, EGFRvIII, sensitized tumor xenografts in mice to cell death, which was augmented by the hydroxymethylglutaryl coenzyme A reductase inhibitor atorvastatin. These results identify a previously undescribed EGFR-mediated prosurvival metabolic pathway and suggest new therapeutic approaches to treating EGFR-activated glioblastomas.

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