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Sci. Signal., 15 December 2009
Vol. 2, Issue 101, p. ra82
[DOI: 10.1126/scisignal.2000446]

RESEARCH ARTICLES

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

Deliang Guo1, Robert M. Prins2, Julie Dang1, Daisuke Kuga1, Akio Iwanami1, Horacio Soto2, Kelly Y. Lin1, Tiffany T. Huang1, David Akhavan1, M. Benjamin Hock1, Shaojun Zhu1, Ava A. Kofman1, Steve J. Bensinger1, William H. Yong1,3, Harry V. Vinters1,4, Steve Horvath5, Andrew D. Watson6, John G. Kuhn7, H. Ian Robins8, Minesh P. Mehta8, Patrick Y. Wen9, Lisa M. DeAngelis10, Michael D. Prados11, Ingo K. Mellinghoff10, Timothy F. Cloughesy3,4, and Paul S. Mischel1,3,12*

1 Department of Pathology and Laboratory Medicine, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA.
2 Department of Surgery, Division of Neurosurgery, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA.
3 Henry Singleton Brain Tumor Program and Jonsson Comprehensive Cancer Center, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA.
4 Department of Neurology, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA.
5 Departments of Human Genetics and Biostatistics, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA.
6 Department of Medicine, Division of Cardiology, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA.
7 University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
8 University of Wisconsin-Madison, Madison, WI 53711, USA.
9 Dana-Farber Cancer Institute, Boston, MA 02115, USA.
10 Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
11 University of California, San Francisco, San Francisco, CA 94143, USA.
12 Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA.

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.

* To whom correspondence should be addressed. E-mail: pmischel{at}mednet.ucla.edu

Citation: D. Guo, R. M. Prins, J. Dang, D. Kuga, A. Iwanami, H. Soto, K. Y. Lin, T. T. Huang, D. Akhavan, M. B. Hock, S. Zhu, A. A. Kofman, S. J. Bensinger, W. H. Yong, H. V. Vinters, S. Horvath, A. D. Watson, J. G. Kuhn, H. I. Robins, M. P. Mehta, P. Y. Wen, L. M. DeAngelis, M. D. Prados, I. K. Mellinghoff, T. F. Cloughesy, P. S. Mischel, EGFR Signaling Through an Akt-SREBP-1–Dependent, Rapamycin-Resistant Pathway Sensitizes Glioblastomas to Antilipogenic Therapy. Sci. Signal. 2, ra82 (2009).

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