title: Dual blockade of EGFR and c-Met abrogates redundant signaling and proliferation in head and neck carcinoma cells.
abstract: OBJECTIVE
  Head and neck squamous cell carcinoma (HNSCC) is usually fatal, and innovative approaches targeting growth pathways are necessary to effectively treat this disease. Both the epidermal growth factor receptor (EGFR) and the hepatocyte growth factor (HGF)/c-Met pathways are overexpressed in HNSCC and initiate similar downstream signaling pathways. c-Met may act in consort with EGFR and/or be activated as a compensatory pathway in the presence of EGFR blockade.
  
  
  METHODS
  Expression levels of EGFR and c-Met were determined by Western analysis in HNSCC cell lines and correlated with antitumor responses to inhibitors of these pathways.
  
  
  RESULTS
  Combining the c-Met inhibitor PF2341066 with the EGFR inhibitor gefitinib abrogated HNSCC cell proliferation, invasion, and wound healing significantly more than inhibition of each pathway alone in HNSCC cell lines. When both HGF and the EGFR ligand, TGF-α, were present in vitro, P-AKT and P-MAPK expression were maximally inhibited by targeting both EGFR and c-Met pathways, suggesting that c-Met or EGFR can compensate when phosphorylation of the other receptor is inhibited. We also showed that TGF-α can induce phosphorylation of c-Met over sixfold by 8 hours in the absence of HGF, supporting a ligand-independent mechanism. Combined targeting of c-Met and EGFR resulted in an enhanced inhibition of tumor volumes accompanied by a decreased number of proliferating cells and increased apoptosis compared with single agent treatment in vivo.
  
  
  CONCLUSIONS
  Together, these results suggest that dual blockade of c-Met and EGFR may be a promising clinical therapeutic strategy for treating HNSCC.
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Xu
authors.forename: Laura P
authors.initials: LP
authors.lastname: Stabile
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Gubish
authors.forename: William E
authors.initials: WE
authors.lastname: Gooding
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
authors.forename: Jill M
authors.initials: JM
authors.lastname: Siegfried
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009361:Neoplasm Invasiveness; D018307:Neoplasms, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D000077195:Squamous Cell Carcinoma of Head and Neck; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C066855:HGF protein, human; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D016211:Transforming Growth Factor alpha; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D000077156:Gefitinib