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Dasatinib Modulates Invasive and Migratory Properties of Canine Osteosarcoma and has Therapeutic Potential in
Kevin Marley1, Justine Gullaba1, Bernard Seguin1
1Department of Clinical Sciences Oregon State University, 105 Magruder Hall, Corvallis OR, 97331, USA.
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.
Insights
Dasatinib effectively inhibited hepatocyte growth factor (HGF)-induced invasion, migration, and viability in canine osteosarcoma (OS) cell lines, suggesting potential clinical benefit for dogs with OS.
Area of Science:
- Veterinary Oncology
- Molecular Biology
- Pharmacology
Background:
- Investigated the link between hepatocyte growth factor (HGF) and metastatic behavior in canine osteosarcoma (OS).
- Examined the efficacy of tyrosine kinase inhibitors (TKIs) crizotinib and dasatinib against HGF-induced metastasis.
- Preliminary clinical observations suggested a benefit of dasatinib in four dogs with OS.
Purpose of the Study:
- To determine if crizotinib and dasatinib can block HGF-induced metastatic behavior in canine OS.
- To assess the impact of these TKIs on MET phosphorylation, matrix metalloproteinase (MMP) production, and cancer cell invasion, migration, and viability.
- To evaluate dasatinib as an adjuvant therapy in canine OS patients.
Main Methods:
- Assessed TKIs' ability to inhibit MET phosphorylation and HGF-induced MMP production in canine OS cell lines.
- Evaluated the effect of TKIs on OS cell invasion, migration, and viability.
- Administered oral dasatinib (0.75 mg/kg) as adjuvant therapy to four dogs with OS.
Main Results:
- HGF significantly increased cell migration and invasion in canine OS cell lines.
- Dasatinib suppressed OS cell viability and HGF-induced invasion and migration.
- Crizotinib reduced migration and MMP-9 production but did not inhibit invasion or viability.
Conclusions:
- Exogenous HGF increases invasion, migration, and viability of canine OS cell lines.
- Dasatinib more uniformly inhibited HGF-driven increases in viability and metastatic behaviors compared to crizotinib.
- These findings suggest a potential clinical benefit of adjuvant dasatinib treatment for dogs with osteosarcoma.
