Quantitative analysis of the EGFRvIII mutant receptor signaling networks in Glioblastoma

Glioblastoma multiforme (GBM) is the most aggressive adult brain tumor and remains incurable despite multimodal intensive treatment regimens. EGFRvIII is a truncated extracellular mutant of the EGF receptor (EGFR) that is commonly found in GBMs and confers tumorigenic behavior. Although much work has been done over the past decade to elucidate pathways involved in EGFRvIII receptor signaling, the global map of the signaling networks that it activates remains incomplete, making it difficult to assess downstream components involved in EGFRvill-mediated transformation. To gain a molecular understanding of the mechanisms by which EGFRvIII acts, we have employed a mass spectrometry-based phosphoproteomic approach to quantitatively map cellular signaling events activated by this receptor. Using this approach, we have determined the major downstream pathways activated as a function of titrated EGFRvIII receptor levels. This analysis highlighted several aspects of EGFRvIII tumor biology, including crosstalk between EGFRvIII and other receptor tyrosine kinases. Specifically, we have identified the c-Met receptor as a co-target in the treatment of EGFRvIII positive GBM cells, and have shown that an EGFR and c-Met combination inhibitor strategy may be applicable in overcoming the poor efficacy of EGFR kinase inhibitor monotherapy in GBM patients. We then went on to investigate the mechanisms by which signaling networks are regulated in response to site-specific tyrosine mutations on EGFRvIII. This analysis has revealed a receptor compensation mechanism that is capable of restoring network architecture, upon the loss of a major tyrosine phosphorylation site on EGFRvIII.

Department dc:contributor.department

Massachusetts Institute of Technology. Biological Engineering Division.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2008

Author dc:creator

• Huang, Hua Ming Paul

Advisor dc:contributor.advisor

• Forest M. White.

• Biological Engineering Division.

Statement dc:rights

• MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/45382

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/45382