title: Radiation-induced dimer formation of EGFR: implications for the radiosensitizing effect of cetuximab.
abstract: OBJECTIVE
  The purpose of this study was to investigate whether radiation induces ligand-independent dimerization of epidermal growth factor receptor (EGFR) and explore the possible role of radiation-induced receptor dimerization in the radiosensitizing effect of cetuximab.
  
  
  METHODS
  The human vulvar squamous cell carcinoma cell line A431 was used. The dimerization and activation of EGFR were quantified using immunoprecipitation, a western blotting analysis, and a chemical cross-linking analysis with dithiobis-sulfosuccinimidyl propionate.
  
  
  RESULTS
  Irradiation at a dose of 2 Gy induced the autophosphorylation of EGFR. Consistent with autophosphorylation, a 360-kDa polypeptide, corresponding to the size of the EGFR dimer, was detected in addition to an EGFR monomer. Radiation also induced hetero-dimerization between EGFR and HER2/neu. Cetuximab combined with radiation inhibited radiation-induced autophosphorylation of EGFR, and inhibited radiation-induced homo-dimerization of EGFR. However, cetuximab incompletely inhibited radiation-induced hetero-dimerization between EGFR and HER2.
  
  
  CONCLUSIONS
  The results of this investigation suggest that radiation-induced homo- and/or hetero-dimerization between EGFR and/or HER2 might be involved in the radioresponse of cancer cells.
authors.affiliation: Department of Radiation Oncology, National cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. takimoto@east.ncc.go.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kiyozuka
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Akimoto
authors.forename: Mika
authors.initials: M
authors.lastname: Fukutome
authors.forename: Atsushi
authors.initials: A
authors.lastname: Motegi
authors.forename: Norio
authors.initials: N
authors.lastname: Mitsuhashi
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D000068818:Cetuximab; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D055503:Protein Multimerization / Q000528:radiation effects; D011499:Protein Processing, Post-Translational; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D066246:ErbB Receptors; D011838:Radiation-Sensitizing Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: A431 cells; EGFR; cetuximab; dimerization; radiation; radiosensitivity