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EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy.

Science signaling (2009-12-17)
Deliang Guo, Robert M Prins, Julie Dang, Daisuke Kuga, Akio Iwanami, Horacio Soto, Kelly Y Lin, Tiffany T Huang, David Akhavan, M Benjamin Hock, Shaojun Zhu, Ava A Kofman, Steve J Bensinger, William H Yong, Harry V Vinters, Steve Horvath, Andrew D Watson, John G Kuhn, H Ian Robins, Minesh P Mehta, Patrick Y Wen, Lisa M DeAngelis, Michael D Prados, Ingo K Mellinghoff, Timothy F Cloughesy, Paul S Mischel
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.

MATERIALS
Product Number
Brand
Product Description

Supelco
Butylated Hydroxytoluene, Pharmaceutical Secondary Standard; Certified Reference Material
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Rapamycin, Ready Made Solution, 2.5 mg/mL in DMSO (2.74 mM), from Streptomyces hygroscopicus
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Anti-RNA polymerase II Antibody, clone CTD4H8, clone CTD4H8, Upstate®, from mouse
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Normal Mouse IgG, Normal Mouse IgG Polyclonal Antibody control validated for use in Immunoprecipitation & Western Blotting.
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Rapamycin, VETRANAL®, analytical standard