title: Targeting irradiation-induced mitogen-activated protein kinase activation in vitro and in an ex vivo model for human head and neck cancer.
abstract: Despite new radiotherapeutic strategies, radioresistance in head and neck squamous cell carcinoma (HNSCC) remains a major problem. Preclinical model systems are needed to identify resistance mechanisms in this heterogeneous entity.
  
  
  
  We elucidated the interplay among mitogen-activated protein kinase (MAPK)-inhibition, radiation, and p53 mutations in vitro and in a novel ex vivo model derived from vital human HNSCC samples. HNSCC cell lines (p53WT/mut) were treated with the mitogen-activated protein kinase (MEK)-inhibitor PD-0325901 and subsequently irradiated. Radiosensitization was functionally assessed and evaluated in the ex vivo model.
  
  
  
  We observed a pronounced irradiation-induced extracellular signal-regulated kinase (ERK) phosphorylation in 2 cell lines, which was independent of their p53 mutation status and associated with PD-0325901-related radiosensitization in a clonogenic assay. Heterogeneity in irradiation-induced ERK phosphorylation and in radiosensitization after MEK-inhibition was also reflected in the ex vivo model.
  
  
  
  We provide experimental evidence for radiosensitizing effects of PD-0325901 in HNSCC. The ex vivo culture technology might offer a promising tool for individualized drug efficacy testing. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2049-E2061, 2016.
authors.affiliation: Institute of Pathology, Heidelberg University Hospital, Heidelberg, 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, Experimental Head and Neck Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Muller
authors.affiliation: Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Sommer
authors.affiliation: Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Experimental Head and Neck Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Karim
authors.initials: K
authors.lastname: Zaoui
authors.affiliation: Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Lorenz
authors.affiliation: Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wolf
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Experimental Head and Neck Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Sarika
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Wolf
authors.affiliation: Pathology of the University Hospital of Luebeck and Leibniz Research Center Borstel, Luebeck and Borstel, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.affiliation: Department of Radiation Oncology, Heidelberg, Germany.
authors.forename: Klaus-Josef
authors.initials: KJ
authors.lastname: Weber
authors.affiliation: Department of Oral and Maxillofacial Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Kolja
authors.initials: K
authors.lastname: Freier
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Experimental Head and Neck Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Plinkert
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Experimental Head and Neck Oncology, Heidelberg University Hospital, Heidelberg, Germany.|Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hess
authors.affiliation: Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.|Institute of Pathology, Technical University Munich (TUM), Munich, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
mesh_terms: D000328:Adult; D000368:Aged; D001549:Benzamides / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006258:Head and Neck Neoplasms / Q000532:radiotherapy*; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D001549:Benzamides; D011838:Radiation-Sensitizing Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C506614:mirdametinib; D004159:Diphenylamine; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: ex vivo model; head and neck cancer; mitogen-activated protein (MAP) kinase signaling pathway; mitogen-activated protein kinase (MEK) inhibitor; p53 mutations; radioresistance