title: Dasatinib Modulates Invasive and Migratory Properties of Canine Osteosarcoma and has Therapeutic Potential in Affected Dogs.
abstract: BACKGROUND
  This investigation sought to elucidate the relationship between hepatocyte growth factor (HGF)-induced metastatic behavior and the tyrosine kinase inhibitors (TKIs) crizotinib and dasatinib in canine osteosarcoma (OS). Preliminary evidence of an apparent clinical benefit from adjuvant therapy with dasatinib in four dogs is described.
  
  
  METHODS
  The inhibitors were assessed for their ability to block phosphorylation of MET; reduce HGF-induced production of matrix metalloproteinase (MMP); and prevent invasion, migration, and cell viability in canine OS cell lines. Oral dasatinib (0.75 mg/kg) was tested as an adjuvant therapy in four dogs with OS.
  
  
  RESULTS
  Constitutive phosphorylation of MET was detected in two cell lines, and this was unaffected by 20-nM incubation with either dasatinib or crizotinib. Incubation of cell lines with HGF (MET ligand) increased cell migration and invasion in both cell lines and increased MMP-9 activity in one. Dasatinib suppressed OS cell viability and HGF-induced invasion and migration, whereas crizotinib reduced migration and MMP-9 production but did not inhibit invasion or viability.
  
  
  CONCLUSIONS
  Invasion, migration, and viability of canine OS cell lines are increased by exogenous HGF. HGF induces secretion of different forms of MMP in different cell lines. The HGF-driven increase in viability and metastatic behaviors we observed are more uniformly inhibited by dasatinib. These observations suggest a potential clinical benefit of adjuvant dasatinib treatment for dogs with OS.
authors: Department of Clinical Sciences Oregon State University, 105 Magruder Hall, Corvallis OR, 97331, USA. Electronic address: kevin.marley@oregonstate.edu.
authors: Kevin
authors: K
authors: Marley
authors: Department of Clinical Sciences Oregon State University, 105 Magruder Hall, Corvallis OR, 97331, USA. Electronic address: jgullaba@purdue.edu.
authors: Justine
authors: J
authors: Gullaba
authors: Department of Clinical Sciences Oregon State University, 105 Magruder Hall, Corvallis OR, 97331, USA. Electronic address: Bernard.Seguin@colostate.edu.
authors: Bernard
authors: B
authors: Seguin
authors: Department of Clinical Sciences Oregon State University, 105 Magruder Hall, Corvallis OR, 97331, USA. Electronic address: Howard.gelberg@oregonstate.edu.
authors: Howard B
authors: HB
authors: Gelberg
authors: Department of Clinical Sciences Oregon State University, 105 Magruder Hall, Corvallis OR, 97331, USA. Electronic address: sch_726@yahoo.com.
authors: Stuart C
authors: SC
authors: Helfand