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

研究成果: Article査読

243 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)2264-2273
ページ数10
ジャーナルPLoS Medicine
3
12
DOI
出版ステータスPublished - 2006 12
外部発表はい

ASJC Scopus subject areas

  • 医学(全般)

フィンガープリント

「Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル