EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy Academic Article uri icon

Overview

MeSH Major

  • Antineoplastic Agents
  • Brain Neoplasms
  • Glioblastoma
  • Lipogenesis
  • Proto-Oncogene Proteins c-akt
  • Quinazolines
  • Receptor, Epidermal Growth Factor
  • Signal Transduction
  • Sirolimus
  • Sterol Regulatory Element Binding Protein 1

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.

publication date

  • December 15, 2009

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2978002

Digital Object Identifier (DOI)

  • 10.1126/scisignal.2000446

PubMed ID

  • 20009104

Additional Document Info

start page

  • ra82

volume

  • 2

number

  • 101