EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy.
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.
Guo
Deliang
D
1Department of Pathology and Laboratory Medicine, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA.
Prins
Robert M
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Dang
Julie
J
Kuga
Daisuke
D
Iwanami
Akio
A
Soto
Horacio
H
Lin
Kelly Y
KY
Huang
Tiffany T
TT
Akhavan
David
D
Hock
M Benjamin
MB
Zhu
Shaojun
S
Kofman
Ava A
AA
Bensinger
Steve J
SJ
Yong
William H
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Vinters
Harry V
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Horvath
Steve
S
Watson
Andrew D
AD
Kuhn
John G
JG
Robins
H Ian
HI
Mehta
Minesh P
MP
Wen
Patrick Y
PY
DeAngelis
Lisa M
LM
Prados
Michael D
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Mellinghoff
Ingo K
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Cloughesy
Timothy F
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Mischel
Paul S
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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*
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