The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo.
Dasatinib is an oral potent adenosine triphosphate (ATP)-competitive inhibitor of BCR-ABL, cKIT, platelet-derived growth factor receptor, and SRC family kinases (SFKs), which has demonstrated high efficiency in patients with imatinib-resistant chronic myelogenous leukemia. Here, we show that dasatinib weakly affects platelet activation by thrombin or adenosine diphosphate but is a potent inhibitor of platelet signaling and functions initiated by collagen or FcgammaRIIA cross-linking, which require immunoreceptor tyrosine-based activation motif phosphorylation by SFKs. Accordingly, dasatinib treatment rapidly decreases the volume of thrombi formed under arterial flow conditions in whole blood from patients or mice perfused over a matrix of collagen. Moreover, treatment of mice with dasatinib increases the tail bleeding time in a dose-dependent manner. Interestingly, these effects are rapidly reversible after interruption of the treatment. Our data clearly demonstrate that, in contrast to imatinib, dasatinib affects platelet functions in vitro and in vivo, which has important implications in clinic and could explain increased risks of bleeding observed in patients. Moreover, dasatinib efficiently prevents platelet activation mediated by FcgammaRIIA cross-linking and by sera from patients with heparin-induced thrombocytopenia, suggesting that reversible antiplatelet agents acting as ATP-competitive inhibitors of SFKs may be of therapeutic interest in the treatment of this pathology.
Gratacap
Marie-Pierre
MP
Département d'Oncogenèse, Signalisation et Innovation Thérapeutique, Université Toulouse III Paul Sabatier, Inserm U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
Martin
Valérie
V
Valéra
Marie-Cécile
MC
Allart
Sophie
S
Garcia
Cédric
C
Sié
Pierre
P
Recher
Christian
C
Payrastre
Bernard
B
D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D001792:Blood Platelets / Q000187:drug effects*; D000069439:Dasatinib; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D000069439:Dasatinib