title: Combination of mTOR and EGFR targeting in an orthotopic xenograft model of head and neck cancer.
abstract: OBJECTIVE
  Recent preclinical and clinical studies on head and neck squamous cell carcinoma (HNSCC) revealed synergistic effects when combining anti-EGFR agents with conventional chemotherapeutic drugs. Activation of the PI3-kinase/AKT/mTOR signaling pathway has been identified as an important mechanism implicated in tumor progression and resistance to EGFR inhibitors. The aim of this study was to investigate the effects of combining the mTOR inhibitor temsirolimus (Tem) with the anti-EGFR agent cetuximab (Cet) and conventional chemotherapeutic drugs (cisplatin and fluorouracil (C/F)) on an orthotopic model of HNSCC.
  
  
  METHODS
  Preclinical in vivo study.
  
  
  METHODS
  We evaluated the anti-tumor efficacy (measured tumor volume) of Tem, Cet, and C/F, administered alone or in combination. Investigations were performed using a human HNSCC cell line, CAL33, injected into the mouth floor of nude mice.
  
  
  RESULTS
  As compared with the control, the combination of Tem and Cet led to the highest tumor inhibition and induced almost complete tumor growth arrest (P = 0.001). Tem significantly enhanced the impact of the Cet-C/F combination on tumor growth (P < 0.001). The highest inhibitory effects of treatments on cell proliferation (Ki67 labeling), MAPK (pP42/44 labeling), and PI3K/AKT/mTOR (pS6R labeling) signaling pathways were found with the Tem-Cet association.
  
  
  CONCLUSIONS
  In this orthotopic HNSCC model, the combination of Tem with Cet produced synergistic effects on tumor growth. These results were corroborated by a strong inhibition of both MAPK and PI3K-mTOR signaling pathways.
  
  
  METHODS
  N/A.
authors.affiliation: Institut Universitaire de la Face et du Cou, Clermont-Ferrand, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bozec
authors.affiliation: Department of Oncopharmacology, Clermont-Ferrand, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ebran
authors.affiliation: Department of Histopathology, Centre Jean Perrin, Clermont-Ferrand, France.|ERTICa Research Group, University of Auvergne, Clermont-Ferrand, France.
authors.forename: Nina
authors.initials: N
authors.lastname: Radosevic-Robin
authors.affiliation: Department of Histopathology, Centre Antoine Lacassagne, Nice cedex, Clermont-Ferrand, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Sudaka
authors.affiliation: Department of Medical Oncology, S. Croce General Hospital, Cuneo, Italy.
authors.forename: Martino
authors.initials: M
authors.lastname: Monteverde
authors.affiliation: Department of Histopathology, Centre Antoine Lacassagne, Nice cedex, Clermont-Ferrand, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Toussan
authors.affiliation: Department of Oncopharmacology, Clermont-Ferrand, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Etienne-Grimaldi
authors.affiliation: Department of Medical Oncology, S. Croce General Hospital, Cuneo, Italy.
authors.forename: Cristiana Lo
authors.initials: CL
authors.lastname: Nigro
authors.affiliation: Department of Medical Oncology, S. Croce General Hospital, Cuneo, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Merlano
authors.affiliation: Department of Histopathology, Centre Jean Perrin, Clermont-Ferrand, France.|ERTICa Research Group, University of Auvergne, Clermont-Ferrand, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Penault-Llorca
authors.affiliation: Department of Oncopharmacology, Clermont-Ferrand, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000494:pharmacology / Q000627:therapeutic use; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D066246:ErbB Receptors / Q000187:drug effects*; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: C401859:temsirolimus; C546842:MTOR protein, human; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D000068818:Cetuximab; D002945:Cisplatin; D005472:Fluorouracil; D020123:Sirolimus
keywords: EGFR; PI3KCA; head and neck cancer; mTOR; orthotopic model; targeted therapy; xenograft