title: Synergistic apoptosis in head and neck squamous cell carcinoma cells by co-inhibition of insulin-like growth factor-1 receptor signaling and compensatory signaling pathways.
abstract: BACKGROUND
  In head and neck squamous cell carcinoma (HNSCC), resistance to single-agent targeted therapy may be overcome by co-targeting of compensatory signaling pathways.
  
  
  METHODS
  A targeted drug screen with 120 combinations was used on 9 HNSCC cell lines.
  
  
  RESULTS
  Multiple novel drug combinations demonstrated synergistic growth inhibition. Combining the insulin-like growth factor-1 receptor (IGF-1R) inhibitor, BMS754807, with either the human epidermal growth factor receptor (HER)-family inhibitor, BMS599626, or the Src-family kinase inhibitor, dasatinib, resulted in substantial synergy and growth inhibition. Depending on the cell line, these combinations induced synergistic or additive apoptosis; when synergistic apoptosis was observed, AKT phosphorylation was inhibited to a greater extent than either drug alone. Conversely, when additive apoptosis occurred, AKT phosphorylation was not reduced by the drug combination.
  
  
  CONCLUSIONS
  Combined IGF-1R/HER family and IGF-1R/Src family inhibition may have therapeutic potential in HNSCC. AKT may be a node of convergence between IGF-1R signaling and pathways that compensate for IGF-1R inhibition.
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of Virginia Health System, Charlottesville, Virginia.|Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Axelrod
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Rolando E
authors.initials: RE
authors.lastname: Mendez
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of Virginia Health System, Charlottesville, Virginia.|Department of Biochemistry, National Liver Institute, Menoufiya University, Egypt.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Khalil
authors.affiliation: Department of Pharmacology, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Leimgruber
authors.affiliation: Department of Pharmacology, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Sharlow
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Brian
authors.initials: B
authors.lastname: Capaldo
authors.affiliation: Department of Health Evaluation Sciences, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Mark
authors.initials: M
authors.lastname: Conaway
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Gioeli
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Weber
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Jameson
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002219:Carbamates / Q000008:administration & dosage; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D000069439:Dasatinib / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*; D011720:Pyrazoles / Q000008:administration & dosage; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D014227:Triazines / Q000008:administration & dosage
chemical_list: C545990:BMS 754807; D002219:Carbamates; D011720:Pyrazoles; D014227:Triazines; C545531:(4-((1-(3-fluorophenyl)methyl)-1H-indazol-5-ylamino)-5-methylpyrrolo(2,1-f)(1,2,4)triazin-6-yl)carbamic acid 3-morpholinylmethyl ester; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D000069439:Dasatinib
keywords: combination therapy; compensatory signaling; drug resistance; head and neck squamous cell carcinoma; insulin-like growth factor-1 receptor