The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo

Gratacap, Marie-Pierre; Martin, Valérie; Valera, Marie-Cécile; Allart, Sophie; Garcia, Cédric; Sié, P.; Récher, Christian; Payrastre, Bernard

doi:10.1182/blood-2009-02-205328

Cited by 111 publications

(109 citation statements)

References 44 publications

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“…To test this directly, Wt mice were injected with the SFK inhibitor Dasatinib (5 mg/kg) or vehicle. 29 In line with previous data, 30 we detected an ITAM-specific activation defect in platelets of Dasatinibtreated mice, whereas other signaling pathways were unaffected, confirming the selectivity of the inhibitor (supplemental Figure 4). Surprisingly, injection of 100 mg of INU1 in Dasatinib-treated Wt mice resulted in thrombocytopenia after 2 hours, albeit to a lesser extent than in vehicle-pretreated mice ( Figure 5A).…”

Section: Sfk Activity Is Essential For Inu1-induced Receptor Internalsupporting

confidence: 91%

Targeted downregulation of platelet CLEC-2 occurs through Syk-independent internalization

Lorenz

Stegner

Stritt

et al. 2015

Blood

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Key Points• CLEC-2 can be downregulated from circulating platelets by anti-CLEC-2 antibodies through Src-family kinasedependent internalization.• Platelet-specific Syk deficiency abrogates anti-CLEC-2 antibodies-induced thrombocytopenia, but not CLEC-2 internalization.Platelet aggregation at sites of vascular injury is not only essential for hemostasis, but may also cause acute ischemic disease states such as myocardial infarction or stroke. The hemi-immunoreceptor tyrosine-based activation motif-containing C-type lectinlike receptor 2 (CLEC-2) mediates powerful platelet activation through a Src-and spleen tyrosine kinase (Syk)-dependent tyrosine phosphorylation cascade. Thereby, CLEC-2 not only contributes to thrombus formation and stabilization but also plays a central role in blood-lymphatic vessel development, tumor metastasis, and prevention of inflammatory bleeding, making it a potential pharmacologic target to modulate these processes.We have previously shown that injection of the anti-CLEC-2 antibody, INU1, results in virtually complete immunodepletion of platelet CLEC-2 in mice, which is, however, preceded by a severe transient thrombocytopenia thereby limiting its potential therapeutic use. The mechanisms underlying this targeted CLEC-2 downregulation have remained elusive. Here, we show that INU1-induced CLEC-2 immunodepletion occurs through Srcfamily kinase-dependent receptor internalization in vitro and in vivo, presumably followed by intracellular degradation. In mice with platelet-specific Syk deficiency, INU1-induced CLEC-2 internalization/degradation was fully preserved whereas the associated thrombocytopenia was largely prevented. These results show for the first time that CLEC-2 can be downregulated from the platelet surface through internalization in vitro and in vivo and that this can be mechanistically uncoupled from the associated antibody-induced thrombocytopenia. (Blood. 2015;125(26):4069-4077)

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Section: Sfk Activity Is Essential For Inu1-induced Receptor Internalsupporting

confidence: 91%

Targeted downregulation of platelet CLEC-2 occurs through Syk-independent internalization

Lorenz

Stegner

Stritt

et al. 2015

Blood

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“…Experiments were performed in PRP prepared from citrated blood (aggregation) or heparinized whole blood (adhesion onto VWF). Most laboratory methods have been described previously 12 and are reported in the supplemental Materials. Statistical analysis was performed using the paired or unpaired Student t test (Excel software, *P , .05 and **P , .01).…”

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confidence: 99%

Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions

Levade

David

Garcia

et al. 2014

Blood

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Key Points• Ibrutinib affects collagen and VWF-mediated platelet activation.• The bleeding diathesis correlates with defects in collagen-induced platelet aggregation and firm adhesion on VWF at arterial shear rate.The oral Bruton's tyrosine kinase inhibitor, ibrutinib, has recently demonstrated high efficiency in patients with relapsed B-cell malignancies. Occurrence of bleeding events has been reported in a subgroup of ibrutinib-treated patients. We demonstrate that ibrutinib selectively inhibits platelet signaling and functions downstream of the collagen receptor glycoprotein VI and strongly affects firm platelet adhesion on von Willebrand factor (VWF) under arterial flow. A longitudinal study of 14 patients indicated a correlation between occurrence of bleeding events and decreased platelet aggregation in response to collagen in platelet-rich plasma and firm adhesion on VWF under arterial flow. The addition of 50% untreated platelets was sufficient to efficiently reverse the effects of ibrutinib, and platelet functions recovered after treatment interruption as physiological platelet renewal occurred. These data have important clinical implications and provide a basis for hemostasis management during ibrutinib treatment. (Blood. 2014;124(26):3991-3995) IntroductionThe Bruton tyrosine kinase (Btk) is an essential actor downstream of the B-cell receptor, and its covalent inhibitor, ibrutinib, has recently been approved for therapies of relapsed chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). [1][2][3][4][5][6][7][8] Bleeding has been reported in up to 50% of ibrutinib-treated patients. Most events were grade 1 to 2 (spontaneous bruising or petechiae), but in 5% of patients, they were of grade 3 or higher after trauma. [4][5][6] Platelets are the most important blood cells to prevent bleeding after vascular injury. Two Tec family kinases, Btk and Tec, are involved in platelet activation downstream of the collagen receptor glycoprotein VI (GPVI) via phospholipase Cg2 (PLCg2) phosphorylation and activation.9,10 Under arterial shear rate, interaction of platelets with the damaged vessel wall is largely mediated by binding of von Willebrand factor (VWF) to its receptor, the GPIb-IX-V complex. In a mouse model, Btk has been shown to play a role in VWF/GPIb-IX-V-induced platelet activation.11 To further characterize the bleeding events in ibrutinib-treated patients, we investigated the effect of this drug on platelet functions in vitro and ex vivo in 14 patients. Study designFor in vitro experiments, whole blood, platelet-rich plasma (PRP), or washed platelets from healthy donors free of antiplatelet medication were preincubated with ibrutinib (PCI-32765; Selleckchem) or dimethylsulfoxide for 10 or 30 minutes as indicated. For ex vivo experiments, blood samples were obtained before and 2 to 4 weeks after starting ibrutinib treatment (Imbruvica; Janssen-Cilaq Laboratories) in patients with CLL (420 mg daily) or MCL (560 mg daily) [4][5][6] (French compassionate use program) after informed consent, in ...

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“…Dasatinib inhibits the production of osteoclasts and tumor-associated macrophages, as well as the functional activities of osteoclasts, platelets, T cells and natural killer cells. [3][4][5][6][7] As these cell types do not express BCR-ABL, inhibition of SFK members such as LYN, or other kinase targets, is likely responsible for the effects of dasatinib on these cells.…”

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confidence: 99%

Dasatinib promotes ATRA-induced differentiation of AML cells

et al. 2009

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are sensitive to NMD in primary AML. Consequently, these AML cases do not express the predicted truncated WT1 proteins. In these AML cases, mutations in WT1 may result in haploinsufficiency rather than expression of truncated WT1 proteins with impaired function. Haploinsufficiency and impaired function have been proposed as two possible mechanisms by which mutant WT1 may affect normal hematopoietic development. Surprisingly, in the WT1 mutant AML cases the wild-type WT1 protein is expressed at relatively high levels. Although, this phenomena has been shown in sporadic Wilms' tumors and some related syndromes, it is currently unclear whether the WT1 protein is pathogenic in these cases or whether it is related to the etiology of the cell of origin. 1

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The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo

Cited by 111 publications

References 44 publications

Targeted downregulation of platelet CLEC-2 occurs through Syk-independent internalization

Targeted downregulation of platelet CLEC-2 occurs through Syk-independent internalization

Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions

Dasatinib promotes ATRA-induced differentiation of AML cells

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