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

TitleQuantitative analysis of EGFRvIII cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma.
Publication TypeJournal Article
Year of Publication2007
AuthorsHuang, PH, Mukasa, A, Bonavia, R, Flynn, RA, Brewer, ZE, Cavenee, WK, Furnari, FB, White, FM
JournalProc Natl Acad Sci U S A
Date Published2007 Jul 31
KeywordsAnimals, Cell Line, Tumor, Drug Resistance, Neoplasm, Glioblastoma, Humans, Mice, Mice, Nude, Phosphorylation, Protein Kinase Inhibitors, Protein Kinases, Receptor, Epidermal Growth Factor, Signal Transduction, Xenograft Model Antitumor Assays

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.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID17646646
PubMed Central IDPMC1937558
Grant ListP01 CA 95616 / CA / NCI NIH HHS / United States
P60 GM 68762 / GM / NIGMS NIH HHS / United States
U54 CA 112967 / CA / NCI NIH HHS / United States