Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain.

PLoS Med
Authors
Keywords
Abstract

BACKGROUND: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy.

METHODS AND FINDINGS: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors.

CONCLUSIONS: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.

Year of Publication
2006
Journal
PLoS Med
Volume
3
Issue
12
Pages
e485
Date Published
2006 Dec
ISSN
1549-1676
URL
DOI
10.1371/journal.pmed.0030485
PubMed ID
17177598
PubMed Central ID
PMC1702556
Links
Grant list
R01 CA116020 / CA / NCI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States