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 prosurvival metabolic pathway and suggest new therapeutic approaches to treating EGFR-activated glioblastomas.
authors.affiliation: 1Department of Pathology and Laboratory Medicine, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA.
authors.forename: Deliang
authors.initials: D
authors.lastname: Guo
authors.forename: Robert M
authors.initials: RM
authors.lastname: Prins
authors.forename: Julie
authors.initials: J
authors.lastname: Dang
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kuga
authors.forename: Akio
authors.initials: A
authors.lastname: Iwanami
authors.forename: Horacio
authors.initials: H
authors.lastname: Soto
authors.forename: Kelly Y
authors.initials: KY
authors.lastname: Lin
authors.forename: Tiffany T
authors.initials: TT
authors.lastname: Huang
authors.forename: David
authors.initials: D
authors.lastname: Akhavan
authors.forename: M Benjamin
authors.initials: MB
authors.lastname: Hock
authors.forename: Shaojun
authors.initials: S
authors.lastname: Zhu
authors.forename: Ava A
authors.initials: AA
authors.lastname: Kofman
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Bensinger
authors.forename: William H
authors.initials: WH
authors.lastname: Yong
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Watson
authors.forename: John G
authors.initials: JG
authors.lastname: Kuhn
authors.forename: H Ian
authors.initials: HI
authors.lastname: Robins
authors.forename: Minesh P
authors.initials: MP
authors.lastname: Mehta
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.forename: Lisa M
authors.initials: LM
authors.lastname: DeAngelis
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D000077341:Lapatinib; D050155:Lipogenesis / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011799:Quinazolines / Q000627:therapeutic use*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D005227:Fatty Acids; D011799:Quinazolines; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D000077341:Lapatinib; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus