title: Lyn kinase mediates cell motility and tumor growth in EGFRvIII-expressing head and neck cancer.
abstract: OBJECTIVE
  EGF receptor variant III (EGFRvIII) has been detected in several cancers in which tumors expressing this truncated growth factor receptor show more aggressive behavior. The molecular mechanisms that contribute to EGFRvIII-mediated tumor progression that are amenable to targeted therapy are incompletely understood. The present study aimed to better define the role of Src family kinases (SFKs) in EGFRvIII-mediated cell motility and tumor growth of head and neck squamous cell carcinomas (HNSCC).
  
  
  METHODS
  HNSCC models expressing EGFRvIII were treated with dasatinib, a pharmacologic inhibitor of SFKs.
  
  
  RESULTS
  SFK inhibition significantly decreased cell proliferation, migration, and invasion of EGFRvIII-expressing HNSCC cells. Administration of dasatinib to mice bearing EGFRvIII-expressing HNSCC xenografts resulted in a significant reduction of tumor volume compared with controls. Immunoprecipitation with anti-c-Src, Lyn, Fyn, and Yes antibodies followed by immunoblotting for phosphorylation of the SFK activation site (Y416) showed specific activation of Lyn kinase in EGFRvIII-expressing HNSCC cell lines and human HNSCC tumor specimens. Selective inhibition of Lyn using siRNA decreased cell migration and invasion of EGFRvIII-expressing HNSCCs compared with vector control cells.
  
  
  CONCLUSIONS
  These findings show that Lyn mediates tumor progression of EGFRvIII-expressing HNSCCs in which strategies to inhibit SFK may represent an effective therapeutic strategy.
authors.affiliation: Departments of Otolaryngology and Pathology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Wheeler
authors.forename: Elena M
authors.initials: EM
authors.lastname: Morariu
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Bednash
authors.forename: Charlton G
authors.initials: CG
authors.lastname: Otte
authors.forename: Raja R
authors.initials: RR
authors.lastname: Seethala
authors.forename: Simion I
authors.initials: SI
authors.lastname: Chiosea
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D000081247:CSK Tyrosine-Protein Kinase; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D018450:Disease Progression; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000276:immunology; D051575:Proto-Oncogene Proteins c-yes / Q000276:immunology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D011897:Random Allocation; D000077195:Squamous Cell Carcinoma of Head and Neck; D013844:Thiazoles / Q000494:pharmacology; D014183:Transplantation, Heterologous; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D011743:Pyrimidines; D034741:RNA, Small Interfering; D013844:Thiazoles; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D051575:Proto-Oncogene Proteins c-yes; C489834:YES1 protein, human; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D000069439:Dasatinib