The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo
The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo
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DOI：
10.1182/blood-2011-10-386417
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发表时间：
2012-02-02
期刊：
影响因子：
20.3
通讯作者：
Burger, Jan A.
中科院分区：
文献类型：
--
作者：
Ponader, Sabine;Chen, Shih-Shih;Burger, Jan A.
B细胞受体(BCR)信号转导通路在包括慢性淋巴细胞性白血病(CLL)在内的多种B细胞恶性肿瘤的发病机制中发挥重要作用，并可作为BCR相关蛋白的抑制剂，如酪氨酸激酶(BTK)等。PCI-32765是一种选择性的、不可逆的BTK抑制剂，是一种新型的分子靶向药物，适用于B细胞恶性肿瘤患者，尤其适用于慢性淋巴细胞性白血病患者。在本研究中，我们通过体外和体内模型分析了pCI-32765在慢性淋巴细胞性白血病中的作用机制，并对接受pCI-32765治疗的患者标本进行了相关研究。PCI-32765显著抑制组织归巢趋化因子(CXCL12、CXCL13)对慢性淋巴细胞性白血病细胞的存活、DNA合成和迁移。在体外和体内，pCI-32765还下调慢性淋巴细胞性白血病细胞分泌bcr依赖的趋化因子(CCl_3、CCl_4)。在过继转移性慢性淋巴细胞性白血病小鼠模型中，pCI-32765影响疾病进展。在这个模型中，pCI-32765引起一过性早期淋巴细胞增多，并通过体重、发展、肝包膜肿大的程度和存活率来评估慢性淋巴细胞性白血病的进展。我们的数据表明，PCI32765有效地抑制了CLL细胞的迁移和存活，这可能解释了这种新的靶向药物的一些特有的临床活性。(血。2012年；119(5)：1182-1189)
B-cell receptor (BCR) signaling is a critical pathway in the pathogenesis of several B-cell malignancies, including chronic lymphocytic leukemia (CLL), and can be targeted by inhibitors of BCR-associated kinases, such as Bruton tyrosine kinase (Btk). PCI-32765, a selective, irreversible Btk inhibitor, is a novel, molecularly targeted agent for patients with B-cell malignancies, and is particularly active in patients with CLL. In this study, we analyzed the mechanism of action of PCI-32765 in CLL, using in vitro and in vivo models, and performed correlative studies on specimens from patients receiving therapy with PCI-32765. PCI-32765 significantly inhibited CLL cell survival, DNA synthesis, and migration in response to tissue homing chemokines (CXCL12, CXCL13). PCI-32765 also down-regulated secretion of BCR-dependent chemokines (CCL3, CCL4) by the CLL cells, both in vitro and in vivo. In an adoptive transfer TCL1 mouse model of CLL, PCI-32765 affected disease progression. In this model, PCI-32765 caused a transient early lymphocytosis, and profoundly inhibited CLL progression, as assessed by weight, development, and extent of hepatospenomegaly, and survival. Our data demonstrate that PCI32765 effectively inhibits CLL cell migration and survival, possibly explaining some of the characteristic clinical activity of this new targeted agent. (Blood. 2012;119(5):1182-1189)