1. Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain.
- Author
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Lee JC, Vivanco I, Beroukhim R, Huang JH, Feng WL, DeBiasi RM, Yoshimoto K, King JC, Nghiemphu P, Yuza Y, Xu Q, Greulich H, Thomas RK, Paez JG, Peck TC, Linhart DJ, Glatt KA, Getz G, Onofrio R, Ziaugra L, Levine RL, Gabriel S, Kawaguchi T, O'Neill K, Khan H, Liau LM, Nelson SF, Rao PN, Mischel P, Pieper RO, Cloughesy T, Leahy DJ, Sellers WR, Sawyers CL, Meyerson M, and Mellinghoff IK
- Subjects
- Animals, Astrocytes drug effects, Astrocytes metabolism, Binding Sites drug effects, Cell Line, Tumor, Cell Survival drug effects, Cell Survival genetics, Cells, Cultured, ErbB Receptors chemistry, ErbB Receptors metabolism, Erlotinib Hydrochloride, Gene Expression Regulation, Neoplastic drug effects, Glioblastoma genetics, Glioblastoma pathology, Humans, Mice, Mice, Nude, Models, Molecular, NIH 3T3 Cells, Neoplasms, Experimental genetics, Neoplasms, Experimental metabolism, Neoplasms, Experimental pathology, Phosphorylation, Protein Binding, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors metabolism, Protein Kinase Inhibitors pharmacology, Protein Structure, Tertiary, Quinazolines chemistry, Quinazolines metabolism, Reverse Transcriptase Polymerase Chain Reaction, Transfection, ErbB Receptors genetics, Mutation, Missense, Quinazolines pharmacology
- 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.
- Published
- 2006
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