Preclinical evaluation of dasatinib, a potent Src kinase inhibitor, in melanoma cell lines.
BACKGROUND
Metastatic melanoma is a highly chemotherapy resistant tumour. The use of newer targeted therapies alone and in combination with chemotherapy may offer new hope of improving response to treatment. Dasatinib, a multi-target kinase inhibitor, is currently approved for the treatment of chronic myeloid leukaemia and has shown promising results in preclinical studies in a number of solid tumours.


METHODS
We examined the effects of dasatinib on proliferation, chemo-sensitivity, cell cycle arrest, apoptosis, migration and invasion in human melanoma cell lines. Expression and activation of Src kinase, FAK and EphA2 were also examined in the melanoma cells.


RESULTS
Dasatinib inhibited growth of three of the five melanoma cell lines. Comparison with sorafenib showed that in these three cell lines dasatinib inhibited growth at lower concentrations than sorafenib. Dasatinib in combination with the chemotherapy drug temozolomide showed greater efficacy than either drug alone. Dasatinib induced cell cycle arrest and apoptosis and significantly inhibited cell migration and invasion of melanoma cells. Dasatinib inhibition of proliferation was associated with reduced phosphorylation of Src kinase, while decreased phosphorylation of FAK was implicated in dasatinib-mediated inhibition of migration and invasion in melanoma cells.


CONCLUSIONS
Dasatinib has both anti-proliferative and anti-invasive effects in melanoma cells and combined with chemotherapy may have clinical benefit in the treatment of malignant melanoma.
Eustace
Alex J
AJ
National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland. Alex.eustace@dcu.ie
Crown
John
J
Clynes
Martin
M
O'Donovan
Norma
N
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000069439:Dasatinib; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors; D000077157:Sorafenib; D000077204:Temozolomide; D013844:Thiazoles / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D013844:Thiazoles; D009536:Niacinamide; D003606:Dacarbazine; D000077157:Sorafenib; D036104:Receptor, EphA2; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D000069439:Dasatinib; D000077204:Temozolomide