title: Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain.
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.
  
  
  RESULTS
  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.
authors.affiliation: Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Lee
authors.forename: Igor
authors.initials: I
authors.lastname: Vivanco
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Julie H Y
authors.initials: JH
authors.lastname: Huang
authors.forename: Whei L
authors.initials: WL
authors.lastname: Feng
authors.forename: Ralph M
authors.initials: RM
authors.lastname: DeBiasi
authors.forename: Koji
authors.initials: K
authors.lastname: Yoshimoto
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: King
authors.forename: Phioanh
authors.initials: P
authors.lastname: Nghiemphu
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yuza
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.forename: Heidi
authors.initials: H
authors.lastname: Greulich
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
authors.forename: J Guillermo
authors.initials: JG
authors.lastname: Paez
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Peck
authors.forename: David J
authors.initials: DJ
authors.lastname: Linhart
authors.forename: Karen A
authors.initials: KA
authors.lastname: Glatt
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Robert
authors.initials: R
authors.lastname: Onofrio
authors.forename: Liuda
authors.initials: L
authors.lastname: Ziaugra
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Keith
authors.initials: K
authors.lastname: O'Neill
authors.forename: Haumith
authors.initials: H
authors.lastname: Khan
authors.forename: Linda M
authors.initials: LM
authors.lastname: Liau
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.forename: P Nagesh
authors.initials: PN
authors.lastname: Rao
authors.forename: Paul
authors.initials: P
authors.lastname: Mischel
authors.forename: Russell O
authors.initials: RO
authors.lastname: Pieper
authors.forename: Tim
authors.initials: T
authors.lastname: Cloughesy
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Leahy
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors