title: Predictive value of hypoxia, proliferation and tyrosine kinase receptors for EGFR-inhibition and radiotherapy sensitivity in head and neck cancer models.
abstract: OBJECTIVE
  EGFR-inhibitor Cetuximab (C225) improves the efficacy of radiotherapy in only a subgroup of HNSCC patients. Identification of predictive tumor characteristics is essential to improve patient selection.
  
  
  METHODS
  Response to C225 and/or radiotherapy was assessed with tumor growth delay assays in 4 HNSCC xenograft models with varying EGFR-expression levels. Hypoxia and proliferation were quantified with immunohistochemistry and the expression of proteins involved in C225-resistance with Western blot.
  
  
  RESULTS
  EGFR-expression did not predict response to C225 and/or radiotherapy. Reduction of hypoxia by C225 was only observed in SCCNij202, which was highly sensitive to C225. Proliferation changes correlated with response to C225 and C225 combined with radiotherapy, as proliferation decreased after C225 treatment in C225-sensitive SCCNij202 and after combined treatment in SCCNij185, which showed a synergistic effect to combined C225-radiotherapy. Furthermore, C225-resistant SCCNij153 tumors expressed high levels of (activated) HER3 and MET.
  
  
  CONCLUSIONS
  EGFR-expression is needed for C225-response, but is not sufficient to predict response to C225 with or without radiotherapy. However, basal expression of additional growth factor receptors and effects on proliferation, but not hypoxia, correlated with response to combined C225-radiotherapy treatment and are potential clinically relevant predictive biomarkers.
authors: Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, The Netherlands. h.stegeman@rther.umcn.nl
authors: Hanneke
authors: H
authors: Stegeman
authors: Johannes H
authors: JH
authors: Kaanders
authors: Albert J
authors: AJ
authors: van der Kogel
authors: Mari
authors: M
authors: Iida
authors: Deric L
authors: DL
authors: Wheeler
authors: Paul N
authors: PN
authors: Span
authors: Johan
authors: J
authors: Bussink
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D000068818:Cetuximab; D059248:Chemoradiotherapy; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000032:analysis / Q000037:antagonists & inhibitors*; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D011836:Radiation Tolerance; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000068818:Cetuximab