title: Multikinase inhibitors sorafenib and sunitinib as radiosensitizers in head and neck cancer cell lines.
abstract: Radioresistance is a common feature of head and neck squamous cell carcinoma (HNSCC). We previously showed that the irradiation- activated vascular endothelial growth factor (VEGF)-extracellular signal-regulated kinase (ERK)-axis is fundamental for the survival of resistant tumors. In this study, we examined if treatment with potent multikinase (MK) inhibitors, sorafenib and sunitinib, could radiosensitize tumor cells.
  
  
  
  Cultured HNSCC cell lines were treated with inhibitors and subsequently irradiated. Radiosensitizing effects were functionally assessed by annexin-V apoptosis and clonogenic assays and confirmed by Western blot. Additionally, we surveyed human HNSCC tissue microarrays (TMAs) for activated ERK expression.
  
  
  
  Based on combination indexes, we found that combining irradiation with both inhibitors exerted strong and supra-additive antitumor effects on clonogenic survival. Kinase inhibition enhanced irradiation-induced apoptotic rates and inhibited postradiogenic phospho-ERK-expression. Patients with recurrent HNSCC displayed significantly lower extracellular signal-regulated kinase phosphorylation (pERK) levels than relapse-free patients.
  
  
  
  We propose further evaluation of sorafenib and sunitinib as potential radiosensitizing agents in HNSCC treatment. © 2017 Wiley Periodicals, Inc. Head Neck 39: 623-632, 2017.
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.|Institute of Pathology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.|Department of Otorhinolaryngology, Head and Neck Surgery, Experimental Head and Neck Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Affolter
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Gerson
authors.initials: G
authors.lastname: Samosny
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Heimes
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Schneider
authors.affiliation: Institute of Pathology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.|Institute of Pathology, Technical University Munich (TUM), Munich, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Institute of Pathology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.affiliation: Institute of Pathology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Sommer
authors.affiliation: Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Jensen
authors.affiliation: Department of Radiooncology and Radiotherapy, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Arnulf
authors.initials: A
authors.lastname: Mayer
authors.affiliation: Department of Urology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Walburgis
authors.initials: W
authors.lastname: Brenner
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Wolf J
authors.initials: WJ
authors.lastname: Mann
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brieger
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D001707:Biopsy, Needle; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor / Q000187:drug effects; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000008:administration & dosage*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D011379:Prognosis; D011758:Pyrroles / Q000008:administration & dosage*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D018570:Risk Assessment; D000077157:Sorafenib; D000077195:Squamous Cell Carcinoma of Head and Neck; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D010671:Phenylurea Compounds; D011758:Pyrroles; D011838:Radiation-Sensitizing Agents; D009536:Niacinamide; D000077157:Sorafenib; D000077210:Sunitinib
keywords: head and neck cancer; human head and neck squamous cell carcinoma (HNSCC); mitogen-activated protein kinase (MAPK) signaling pathway; multikinase inhibitor; radioresistance; tissue microarray