Science signaling 2009,
Guo, Deliang; Prins, Robert M; Dang, Julie; Kuga, Daisuke; Iwanami, Akio; Soto, Horacio; Lin, Kelly Y; Huang, Tiffany T; Akhavan, David; Hock, M Benjamin; Zhu, Shaojun; Kofman, Ava A; Bensinger, Steve J; Yong, William H; Vinters, Harry V; Horvath, Steve; Watson, Andrew D; Kuhn, John G; Robins, H Ian; Mehta, Minesh P; Wen, Patrick Y; DeAngelis, Lisa M; Prados, Michael D; Mellinghoff, Ingo K; Cloughesy, Timothy F; Mischel, Paul S
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.
Diseases/Pathways annotated by Medline MESH:
Brain Neoplasms, Glioblastoma
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Text Mining Data
SREBP-1 — mammalian target of rapamycin: " 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 "
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