title: Combining radiotherapy with MEK1/2, STAT5 or STAT6 inhibition reduces survival of head and neck cancer lines.
abstract: BACKGROUND
  Kinases downstream of growth factor receptors have been implicated in radioresistance and are, therefore, attractive targets to improve radiotherapy outcome in head and neck squamous cell carcinoma (HNSCC) patients.
  
  
  METHODS
  An antibody-based array was used to quantify the expression levels of multiple phospho-kinases involved in growth factor signaling in nine untreated or irradiated HNSCC lines. Radiosensitivity was assessed with clonogenic cell survival assays and correlated with the expression levels of the phospho-kinases. Inhibitors of the kinases that were associated with radiosensitivity were tested for their ability to increase radiosensitivity in the 3 most radioresistant HNSCC lines.
  
  
  RESULTS
  The basal expression of phosphorylated Yes, Src and STAT5A, and the expression after radiotherapy of phosphorylated AKT, MSK1/2, Src, Lyn, Fyn, Hck, and STAT6, were correlated with radiosensitivity in the panel of HNSCC lines. In combination with radiotherapy, inhibitors of AKT, p38 and Src Family Kinases (SFK) were variably able to reduce survival, whereas MEK1/2, STAT5 and STAT6 inhibition reduced survival in all cell lines. The combined effect of radiotherapy and the kinase inhibitors on cell survival was mostly additive, although also supra-additive effects were observed for AKT, MEK1/2, p38 and STAT5 inhibition.
  
  
  CONCLUSIONS
  Kinases of the AKT, MAPK, STAT and SFK pathways correlated with radiosensitivity in a panel of HNSCC lines. Particularly inhibitors against MEK1/2, STAT5 and STAT6 were able to decrease survival in combination with radiotherapy. Hence, inhibitors against these kinases have the potential to improve radiotherapy outcome in HNSCC patients and further research is warranted to confirm this in vivo.
authors.affiliation: Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500, HB Nijmegen, The Netherlands. h.stegeman@rther.umcn.nl.
authors.forename: Hanneke
authors.initials: H
authors.lastname: Stegeman
authors.forename: Johannes H A M
authors.initials: JH
authors.lastname: Kaanders
authors.forename: Marieke M G
authors.initials: MM
authors.lastname: Verheijen
authors.forename: Wenny J M
authors.initials: WJ
authors.lastname: Peeters
authors.forename: Deric L
authors.initials: DL
authors.lastname: Wheeler
authors.forename: Mari
authors.initials: M
authors.lastname: Iida
authors.forename: Reidar
authors.initials: R
authors.lastname: Grénman
authors.forename: Albert J
authors.initials: AJ
authors.lastname: van der Kogel
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects*; D059248:Chemoradiotherapy; D000069439:Dasatinib; D004354:Drug Screening Assays, Antitumor; D006258:Head and Neck Neoplasms / Q000628:therapy*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D000077339:Leflunomide; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; D007093:Imidazoles; D007555:Isoxazoles; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D013844:Thiazoles; D025521:Tumor Suppressor Proteins; C113580:U 0126; C482128:MAP2K2 protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D000077339:Leflunomide; C093642:SB 203580; D000069439:Dasatinib