The effect of Bruton's tyrosine kinase (BTK) inhibitors on collagen-induced platelet aggregation, BTK, and tyrosine kinase expressed in hepatocellular carcinoma (TEC)
The effect of Bruton's tyrosine kinase (BTK) inhibitors on collagen-induced platelet aggregation, BTK, and tyrosine kinase expressed in hepatocellular carcinoma (TEC)
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DOI：
10.1111/ejh.13148
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发表时间：
2018-11-01
影响因子：
3.1
通讯作者：
Chang, Betty Y.
中科院分区：
文献类型：
--
作者：
Chen, Jun;Kinoshita, Taisei;Chang, Betty Y.
目的研究布鲁顿酪氨酸激酶（BTK）和肝细胞癌（TEC）酪氨酸激酶在人血小板中的表达。这些激酶通过胶原受体糖蛋白VI参与血小板活化，并可能发挥重叠功能。在临床研究中，BTK抑制剂（ibrutinib, acalabrutinib, tirabrutinib, zanubrutinib）与出血风险增加相关，这可能是单独抑制BTK或BTK和TEC的结果，尽管TEC在出血风险中的作用尚不清楚。方法采用四种方法测定依鲁替尼和阿卡拉替尼的体外催化活性和结合活性。血小板聚集试验确定抑制剂效力及其与BTK和TEC之间选择性的关系。结果两种抑制剂对BTK的选择性均高于TEC。BTK抑制剂抑制血小板聚集的效力与靶向BTK测定的效力相关，包括在细胞中。在临床相关的血浆浓度下，伊鲁替尼、阿卡拉布替尼和替拉替尼抑制胶原诱导的血小板聚集的程度相似，尽管体外IC不同（50）s。结论BTK抑制是抑制血小板聚集的主要驱动因素。这些抑制剂之间的细微差异表明，只有随机、双盲、安慰剂对照的临床研究才能充分解决不同BTK抑制剂的出血风险。
ObjectivesBruton's tyrosine kinase (BTK) and tyrosine kinase expressed in hepatocellular carcinoma (TEC) are expressed by human platelets. These kinases participate in platelet activation through the collagen receptor glycoprotein VI and may perform overlapping functions. In clinical studies, BTK inhibitors (ibrutinib, acalabrutinib, tirabrutinib, zanubrutinib) have been associated with increased bleeding risk, which may result from inhibition of BTK alone or of both BTK and TEC, although the role of TEC in bleeding risk remains unclear.MethodsHere, in vitro catalytic and binding activities of ibrutinib and acalabrutinib were determined with four assay systems. Platelet aggregation assays determined inhibitor potency and its relationship to selectivity between BTK and TEC.ResultsNeither inhibitor was substantially more selective for BTK over TEC. The potencies at which BTK inhibitors suppressed platelet aggregation correlated with the potencies in on-target BTK assays, including those in cells. At clinically relevant plasma concentration, ibrutinib, acalabrutinib, and tirabrutinib inhibited collagen-induced platelet aggregation to a similar extent, despite differing in vitro IC(50)s.ConclusionsOur results suggest BTK inhibition is the primary driver for inhibition of platelet aggregation. The subtle differences between these inhibitors suggest only randomized, double-blind, placebo-controlled clinical studies can fully address the bleeding risks of different BTK inhibitors.