Quantitative Analysis of EGFRvIII Cellular Signaling Networks Reveals a Combinatorial Therapeutic Strategy for Glioblastoma

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 31; pp. 12867 - 12872
• Main Authors: Huang, Paul H., Mukasa, Akitake, Bonavia, Rudy, Flynn, Ryan A., Brewer, Zachary E., Cavenee, Webster K., Furnari, Frank B., White, Forest M.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 31-07-2007; National Acad Sciences
• Subjects: Animals; Binding sites; Biological Sciences; Cell Line, Tumor; Cell lines; Dosage; Drug Resistance, Neoplasm - drug effects; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - metabolism; Glioblastoma - pathology; Glioma; Humans; Kinases; Medical treatment; Mice; Mice, Nude; Molecular biology; Mutation; Phosphorylation; Protease inhibitors; Protein Kinase Inhibitors - therapeutic use; Protein Kinases - metabolism; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Receptors; Signal Transduction; Tumor cell line; Tumors; Viability; Xenograft Model Antitumor Assays
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0705158104

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.