title: Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors.
abstract: BACKGROUND
  The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown.
  
  
  METHODS
  We sequenced kinase domains in the EGFR and human EGFR type 2 (Her2/neu) genes and analyzed the expression of EGFR, EGFR deletion mutant variant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We determined the molecular correlates of clinical response, validated them in an independent data set, and identified effects of the molecular abnormalities in vitro.
  
  
  RESULTS
  Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 percent. Pretreatment tissue was available for molecular analysis from 26 patients, 7 of whom had had a response and 19 of whom had rapid progression during therapy. No mutations in EGFR or Her2/neu kinase domains were detected in the tumors. Coexpression of EGFRvIII and PTEN was significantly associated with a clinical response (P<0.001; odds ratio, 51; 95 percent confidence interval, 4 to 669). These findings were validated in 33 patients who received similar treatment for glioblastoma at a different institution (P=0.001; odds ratio, 40; 95 percent confidence interval, 3 to 468). In vitro, coexpression of EGFRvIII and PTEN sensitized glioblastoma cells to erlotinib.
  
  
  CONCLUSIONS
  Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors.
authors.affiliation: Department of Molecular and Medical Pharmacology and Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles 90095-1732, USA.
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
authors.forename: Maria Y
authors.initials: MY
authors.lastname: Wang
authors.forename: Igor
authors.initials: I
authors.lastname: Vivanco
authors.forename: Daphne A
authors.initials: DA
authors.lastname: Haas-Kogan
authors.forename: Shaojun
authors.initials: S
authors.lastname: Zhu
authors.forename: Ederlyn Q
authors.initials: EQ
authors.lastname: Dia
authors.forename: Kan V
authors.initials: KV
authors.lastname: Lu
authors.forename: Koji
authors.initials: K
authors.lastname: Yoshimoto
authors.forename: Julie H Y
authors.initials: JH
authors.lastname: Huang
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Chute
authors.forename: Bridget L
authors.initials: BL
authors.lastname: Riggs
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
authors.forename: Linda M
authors.initials: LM
authors.lastname: Liau
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.forename: P Nagesh
authors.initials: PN
authors.lastname: Rao
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Peck
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Lee
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.forename: David
authors.initials: D
authors.lastname: Stokoe
authors.forename: Michael
authors.initials: M
authors.lastname: Prados
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D004273:DNA, Neoplasm / Q000032:analysis; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D005784:Gene Amplification; D017353:Gene Deletion; D015870:Gene Expression; D018773:Genes, erbB-1; D018734:Genes, erbB-2; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009837:Oligodendroglioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use; D017422:Sequence Analysis, DNA; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C410723:epidermal growth factor receptor VIII; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; D000077156:Gefitinib