Molecular characterization of EGFR and EGFRvIII signaling networks in human glioblastoma tumor xenografts

Hannah Johnson, Amanda M. Del Rosario, Bryan D. Bryson, Mark A. Schroeder, Jann N Sarkaria, Forest M. White

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Glioblastoma multiforme (GBM) is a malignant primary brain tumor with a mean survival of 15 months with the current standard of care. Genetic profiling efforts have identified the amplification, overexpression, and mutation of the wild-type (wt) epidermal growth factor receptor tyrosine kinase (EGFR) in ∼50% of GBM patients. The genetic aberration of wtEGFR is frequently accompanied by the overexpression of a mutant EGFR known as EGFR variant III (EGFRvIII, de2-7EGFR, ΔEGFR), which is expressed in 30% of GBM tumors. The molecular mechanisms of tumorigenesis driven by EGFRvIII overexpression in human tumors have not been fully elucidated. To identify specific therapeutic targets for EGFRvIII driven tumors, it is important to gather a broad understanding of EGFRvIII specific signaling. Here, we have characterized signaling through the quantitative analysis of protein expression and tyrosine phosphorylation across a panel of glioblastoma tumor xenografts established from patient surgical specimens expressing wtEGFR or overexpressing wtEGFR (wtEGFR+) or EGFRvIII (EGFRvIII+). S100A10 (p11), major vault protein, guanylate-binding protein 1(GBP1), and carbonic anhydrase III (CAIII) were identified to have significantly increased expression in EGFRvIII expressing xenograft tumors relative to wtEGFR xenograft tumors. Increased expression of these four individual proteins was found to be correlated with poor survival in patients with GBM; the combination of these four proteins represents a prognostic signature for poor survival in gliomas. Integration of protein expression and phosphorylation data has uncovered significant heterogeneity among the various tumors and has highlighted several novel pathways, related to EGFR trafficking, activated in glioblastoma. The pathways and proteins identified in these tumor xenografts represent potential therapeutic targets for this disease.

Original languageEnglish (US)
Pages (from-to)1724-1740
Number of pages17
JournalMolecular and Cellular Proteomics
Volume11
Issue number12
DOIs
StatePublished - Dec 2012

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Glioblastoma
Epidermal Growth Factor Receptor
Heterografts
Protein-Tyrosine Kinases
Tumors
Neoplasms
Phosphorylation
Proteins
Survival
Carbonic Anhydrase III
epidermal growth factor receptor VIII
Standard of Care
Protein Binding
Brain Neoplasms
Glioma
Aberrations
Tyrosine
Carrier Proteins
Carcinogenesis
Amplification

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Analytical Chemistry

Cite this

Molecular characterization of EGFR and EGFRvIII signaling networks in human glioblastoma tumor xenografts. / Johnson, Hannah; Del Rosario, Amanda M.; Bryson, Bryan D.; Schroeder, Mark A.; Sarkaria, Jann N; White, Forest M.

In: Molecular and Cellular Proteomics, Vol. 11, No. 12, 12.2012, p. 1724-1740.

Research output: Contribution to journalArticle

Johnson, Hannah ; Del Rosario, Amanda M. ; Bryson, Bryan D. ; Schroeder, Mark A. ; Sarkaria, Jann N ; White, Forest M. / Molecular characterization of EGFR and EGFRvIII signaling networks in human glioblastoma tumor xenografts. In: Molecular and Cellular Proteomics. 2012 ; Vol. 11, No. 12. pp. 1724-1740.
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