Quantitative analysis of EGFRvIII cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma

Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12867-72. doi: 10.1073/pnas.0705158104. Epub 2007 Jul 23.

Abstract

Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults and remains incurable despite multimodal intensive treatment regimens. EGFRvIII is a truncated extracellular mutant of the EGF receptor (EGFR) commonly found in GBMs that confers enhanced tumorigenic behavior. To gain a molecular understanding of the mechanisms by which EGFRvIII acts, we have performed a large-scale analysis of EGFRvIII-activated phosphotyrosine-mediated signaling pathways and thereby have identified and quantified 99 phosphorylation sites on 69 proteins. Distinct signaling responses were observed as a function of titrated EGFRvIII receptor levels with the phosphatidylinositol 3-kinase pathway being dominant over the MAPK and STAT3 pathways at a high level of EGFRvIII expression. Within this data set, the activating phosphorylation site on the c-Met receptor was found to be highly responsive to EGFRvIII levels, indicating cross-activation of the c-Met receptor tyrosine kinase by EGFRvIII. To determine the significance of this finding, we devised a combined treatment regimen that used a c-Met kinase inhibitor and either an EGFR kinase inhibitor or cisplatin. This regimen resulted in enhanced cytotoxicity of EGFRvIII-expressing cells compared with treatment with either compound alone. These results suggest that the clinical use of c-Met kinase inhibitors in combination with either EGFR inhibitors or standard chemotherapeutics might represent a previously undescribed therapeutic approach to overcome the observed chemoresistance in patients with GBMs expressing EGFRvIII.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism*
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology
  • Humans
  • Mice
  • Mice, Nude
  • Phosphorylation
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Kinases / metabolism
  • Signal Transduction*
  • Xenograft Model Antitumor Assays

Substances

  • Protein Kinase Inhibitors
  • epidermal growth factor receptor VIII
  • Protein Kinases
  • ErbB Receptors