Epidermal Growth Factor Receptor Activation in Glioblastoma through Novel Missense Mutations in the Extracellular Domain
Feng, Whei L
King, Jennifer C
Thomas, Roman K
Peck, Timothy C
Linhart, David J
Glatt, Karen A
Levine, Ross L
Liau, Linda M
Nelson, Stanley F
Rao, P. Nagesh
Pieper, Russell O
Leahy, Daniel J
Sellers, William R
Sawyers, Charles L
Mellinghoff, Ingo K
Lee, Jeffrey C.
Paez, J. Guillermo
Published Versionhttps://doi.org/10.1371/journal. pmed.0030485
MetadataShow full item record
CitationLee, Jeffrey C., Igor Vivanco, Rameen Beroukhim, Julie H. Y. Huang, Whei L. Feng, Ralph M. DeBiasi, Koji Yoshimoto, et al. 2006. Epidermal Growth Factor Receptor Activation in Glioblastoma through Novel Missense Mutations in the Extracellular Domain. PLoS Medicine 3(12): e485.
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
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.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:4879196
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