EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy Journal Article
| Authors: | Guo, D.; Prins, R. M.; Dang, J.; Kuga, D.; Iwanami, A.; Soto, H.; Lin, K. Y.; Huang, T. T.; Akhavan, D.; Hock, M. B.; Zhu, S.; Kofman, A. A.; Bensinger, S. J.; Yong, W. H.; Vinters, H. V.; Horvath, S.; Watson, A. D.; Kuhn, J. G.; Robins, H. I.; Mehta, M. P.; Wen, P. Y.; De Angelis, L. M.; Prados, M. D.; Mellinghoff, I. K.; Cloughesy, T. F.; Mischel, P. S. |
| Article Title: | EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy |
| 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 prosurvivalmetabolic pathway and suggest new therapeutic approaches to treating EGFR-activated glioblastomas. Copyright 2008 by the American Association for the Advancement of Science; all rights reserved. |
| Keywords: | immunohistochemistry; signal transduction; protein kinase b; promoter region; genetics; erlotinib; nonhuman; antineoplastic agents; brain tumor; brain neoplasms; antineoplastic agent; cell proliferation; mouse; metabolism; mammalia; cell death; cell survival; mus; apoptosis; epidermal growth factor receptor; receptor, epidermal growth factor; cancer cell culture; drug effect; phosphatidylinositol 3 kinase; genetic manipulation; cancer resistance; drug antagonism; glioblastoma; western blotting; protein transport; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; immunoblotting; fatty acids; gene silencing; tumor growth; nick end labeling; quinazolines; atorvastatin; fatty acid; hydrolysis; rapamycin; lapatinib; short hairpin rna; sterol regulatory element binding protein 1; quinazoline derivative; srebf1 protein, human; lipogenesis; thin layer chromatography; gene knockdown techniques; sirolimus |
| Journal Title: | Science Signaling |
| Volume: | 2 |
| Issue: | 101 |
| ISSN: | 1945-0877 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2009-12-15 |
| Start Page: | ra82 |
| Language: | English |
| DOI: | 10.1126/scisignal.2000446 |
| PUBMED: | 20009104 |
| PROVIDER: | scopus |
| PMCID: | PMC2978002 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 3" - "Export Date: 30 November 2010" - "Source: Scopus" |
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