title: Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting.
abstract: OBJECTIVE
  Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous cell carcinoma (HNSCC) where expression levels correlate with decreased survival. Therapies that block EGFR have shown limited efficacy in clinical trials and primarily when combined with standard therapy. The most common form of mutant EGFR (EGFRvIII) has been described in several cancers, chiefly glioblastoma. The present study was undertaken to determine the incidence of EGFRvIII expression in HNSCC and the biological consequences of EGFRvIII on tumor growth in response to EGFR targeting.
  
  
  METHODS
  Thirty-three HNSCC tumors were evaluated by immunostaining and reverse transcription-PCR for EGFRvIII expression. A representative HNSCC cell line was stably transfected with an EGFRvIII expression construct. EGFRvIII-expressing cells and vector-transfected controls were compared for growth rates in vitro and in vivo as well as chemotherapy-induced apoptosis and the consequences of EGFR inhibition using the chimeric monoclonal antibody C225/cetuximab/Erbitux.
  
  
  RESULTS
  EGFRvIII expression was detected in 42% of HNSCC tumors where EGFRvIII was always found in conjunction with wild-type EGFR. HNSCC cells expressing EGFRvIII showed increased proliferation in vitro and increased tumor volumes in vivo compared with vector-transfected controls. Furthermore, EGFRvIII-transfected HNSCC cells showed decreased apoptosis in response to cisplatin and decreased growth inhibition following treatment with C225 compared with vector-transfected control cells.
  
  
  CONCLUSIONS
  EGFRvIII is expressed in HNSCC where it contributes to enhanced growth and resistance to targeting wild-type EGFR. The antitumor efficacy of EGFR targeting strategies may be enhanced by the addition of EGFRvIII-specific blockade.
authors.affiliation: Department of Otolaryngology, and University of Pittsburgh Cancer Institute Biostatistics, University of Pittsburgh, Pennsylvania 15213, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Sok
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Coppelli
authors.forename: Sufi M
authors.initials: SM
authors.lastname: Thomas
authors.forename: Miriam N
authors.initials: MN
authors.lastname: Lango
authors.forename: Sichuan
authors.initials: S
authors.lastname: Xi
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hunt
authors.forename: Maria L
authors.initials: ML
authors.lastname: Freilino
authors.forename: Michael W
authors.initials: MW
authors.lastname: Graner
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Wikstrand
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: William E
authors.initials: WE
authors.lastname: Gooding
authors.forename: Frank B
authors.initials: FB
authors.lastname: Furnari
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009154:Mutation; D009368:Neoplasm Transplantation; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors