Dasatinib alters the metastatic phenotype of B16-OVA melanoma in vivo.
The Src/Abl tyrosine kinase inhibitor dasatinib is an approved chronic myeloid leukemia treatment and is under investigation for solid tumor therapy. Members of the Src family of kinases (SFKs) are involved in the process of metastasis and dasatinib inhibits the migration and invasiveness of human melanoma cell lines in vitro. SFKs are also involved in immune function and angiogenesis, which both contribute to As active and passive immunotherapies continue to be investigated in metastatic melanoma, we investigated possible interactions between kinase inhibitors and immunotherapies. A murine syngenic model of metastatic melanoma in which B16F10 cells expressed ovalbumin (B16-OVA) was employed and the active immunotherapy comprised immunization with an OVA-expressing recombinant fowlpox virus (FPVOVA).Dasatinib did not affect B16-OVA viability, proliferation, migration or soft agar colony formation. However, depending on drug dose and schedule, differences in the metastatic behavior of B16-OVA were observed in vivo after dasatinib therapy. At a dose of 5 mg/kg/day given before tumor challenge, dasatinib therapy reduced the number of pulmonary metastases. Conversely, a higher dose (25 mg/kg/day), did not affect the number of pulmonary metastases and increased the number of extra-pulmonary metastases. Finally, immunization of B16-OVA-bearing mice with FPVOVA reduced the number of lung metastases. Prior treatment of these mice with dasatinib 5 mg/kg/day did not affect the incidence of lung metastases. Although the mechanisms by which dasatinib alters the metastatic behavior of B16-OVA cells in vivo remain to be determined, we hypothesize that dasatinib acts via multiple tumor-extrinsic processes that include immune function and neoangiogenesis.
Fraser
Cara K
CK
Hanson Institute, Adelaide, The University of South Australia, South Australia, Australia.
Lousberg
Erin L
EL
Guerin
Leigh R
LR
Hughes
Timothy P
TP
Brown
Michael P
MP
Diener
Kerrilyn R
KR
Hayball
John D
JD
D000818:Animals; D045744:Cell Line, Tumor; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D005587:Fowlpox virus / Q000235:genetics; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D010047:Ovalbumin; D000069439:Dasatinib