Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma
Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma
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DOI：
10.1182/blood-2011-12-396853
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发表时间：
2012-08-30
期刊：
影响因子：
20.3
通讯作者：
Anderson, Kenneth C.
中科院分区：
文献类型：
--
作者：
Tai, Yu-Tzu;Chang, Betty Y.;Anderson, Kenneth C.
布鲁顿酪氨酸激酶（Btk）在B细胞发育中具有明确的作用，而其在破骨细胞（OC）中的表达进一步表明在破骨细胞生成中的作用。在这里，我们研究了PCI-32765（一种口服和选择性Btk抑制剂）对破骨细胞生成以及骨髓微环境中多发性骨髓瘤（MM）生长的影响。PCI-32765阻断RANKL/M-CSF诱导的OC中Btk和下游PLC-γ 2的磷酸化，导致TRAP 5 b（ED 50 = 17 nM）和骨吸收活性降低。PCI-32765还抑制来自正常供体（ED 50 = 0.5nM）和MM患者的OC和BM基质细胞培养物的多种细胞因子和趋化因子的分泌。它减少了SDF-1诱导的MM细胞迁移，并下调了MM细胞中的MIP 1-α/CCL 3。它还在体外阻断由IL-6或与BM基质细胞或OC共培养触发的MM细胞生长和存活。重要的是，PCI-32765治疗显著抑制了体内MM细胞生长（P <0.03）和SCID小鼠中植入的人骨芯片的MM细胞诱导的骨质溶解。此外，PCI-32765可防止MM患者干细胞样细胞的体外集落形成。总之，这些结果描绘了Btk活化介导骨质溶解和MM细胞生长的功能性后遗症，支持PCI-32765作为MM中的新型治疗剂的评价。2012;120（9）：1877-1887）
Bruton tyrosine kinase (Btk) has a well-defined role in B-cell development, whereas its expression in osteoclasts (OCs) further suggests a role in osteoclastogenesis. Here we investigated effects of PCI-32765, an oral and selective Btk inhibitor, on osteoclastogenesis as well as on multiple myeloma (MM) growth within the BM microenvironment. PCI-32765 blocked RANKL/M-CSF-induced phosphorylation of Btk and downstream PLC-gamma 2 in OCs, resulting in diminished TRAP5b (ED50 = 17nM) and bone resorption activity. PCI-32765 also inhibited secretion of multiple cytokines and chemokines from OC and BM stromal cell cultures from both normal donors (ED50 = 0.5nM) and MM patients. It decreased SDF-1-induced migration of MM cells, and down-regulated MIP1-alpha/CCL3 in MM cells. It also blocked MM cell growth and survival triggered by IL-6 or coculture with BM stromal cells or OCs in vitro. Importantly, PCI-32765 treatment significantly inhibits in vivo MM cell growth (P < .03) and MM cell-induced osteolysis of implanted human bone chips in SCID mice. Moreover, PCI-32765 prevents in vitro colony formation by stem-like cells from MM patients. Together, these results delineate functional sequelae of Btk activation mediating osteolysis and growth of MM cells, supporting evaluation of PCI-32765 as a novel therapeutic in MM. (Blood. 2012;120(9):1877-1887)