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

Jeffrey C. Lee, Igor Vivanco, Rameen Beroukhim, Julie H.Y. Huang, Whei L. Feng, Ralph M. DeBiasi, Koji Yoshimoto, Jennifer C. King, Phioanh Nghiemphu, Yuki Yuza, Qing Xu, Heidi Greulich, Roman K. Thomas, J. Guillermo Paez, Timothy C. Peck, David J. Linhart, Karen A. Glatt, Gad Getz, Robert Onofrio, Liuda ZiaugraRoss L. Levine, Stacey Gabriel, Tomohiro Kawaguchi, Keith O'Neill, Haumith Khan, Linda M. Liau, Stanley F. Nelson, P. Nagesh Rao, Paul Mischel, Russell O. Pieper, Tim Cloughesy, Daniel J. Leahy, William R. Sellers, Charles L. Sawyers, Matthew Meyerson, Ingo K. Mellinghoff

Research output: Contribution to journalArticlepeer-review

226 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2264-2273
Number of pages10
JournalPLoS medicine
Issue number12
StatePublished - Dec 2006
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)


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