Polo-like Kinase 1 (Plk1) as a Novel Drug Target in Chronic Myeloid Leukemia: Overriding Imatinib Resistance with the Plk1 Inhibitor BI 2536
Polo-like Kinase 1 (Plk1) as a Novel Drug Target in Chronic Myeloid Leukemia: Overriding Imatinib Resistance with the Plk1 Inhibitor BI 2536
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DOI：
10.1158/0008-5472.can-09-2181
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发表时间：
2010-02-15
期刊：
影响因子：
11.2
通讯作者：
Valent, Peter
中科院分区：
文献类型：
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作者：
Gleixner, Karoline V.;Ferenc, Veronika;Valent, Peter
在大多数慢性粒细胞白血病（CML）患者中，可以使用BCR/ABL激酶抑制剂伊马替尼控制疾病。然而，在治疗过程中可能会发生对伊马替尼和其他BCR/ABL抑制剂的耐药或不耐受。因此，CML研究的重点是新的靶点和靶向药物。Polo样激酶1（Plk 1）是一种丝氨酸/苏氨酸激酶，在有丝分裂中起重要作用。在这项研究中，我们研究了Plk 1在CML细胞中的表达及其作为治疗靶点的潜在作用。发现Plk 1在CML细胞系K562中以磷酸化形式表达，并且在所有测试患者的原代CML细胞中也是如此。伊马替尼或尼洛替尼（AMN 107）抑制BCR/ABL导致CML细胞中Plk 1蛋白表达降低，表明BCR/ABL促进Plk 1生成。通过小干扰RNA方法沉默CML细胞中的Plk 1，随后是细胞周期停滞和凋亡。此外，发现Plk 1靶向药物BI 2536可抑制伊马替尼敏感和伊马替尼耐药CML细胞（包括携带BCR/ABL T315突变的白血病细胞）的增殖，具有合理的IC 50值（1-50 nmol/L）。BI 2536对CML细胞的生长抑制作用与细胞周期阻滞和细胞凋亡相关。此外，发现BI 2536与伊马替尼和尼洛替尼在CML细胞中产生生长抑制方面具有协同作用。总之，Plk 1在CML细胞中表达，可能是伊马替尼敏感和伊马替尼耐药CML的一个新的、有趣的靶点。Cancer Res; 70（4）; 1513-23. (C)2010年AACR。
In most patients with chronic myeloid leukemia (CML), the disease can be kept under control using the BCR/ABL kinase inhibitor imatinib. Nevertheless, resistance or intolerance to imatinib and other BCR/ABL inhibitors may occur during therapy. Therefore, CML research is focusing on novel targets and targeted drugs. Polo-like kinase 1 (Plk1) is a serine/threonine kinase that plays an essential role in mitosis. In this study, we examined the expression of Plk1 in CML cells and its potential role as a therapeutic target. Plk1 was found to be expressed in phosphorylated form in the CML cell line K562 as well as in primary CML cells in all patients tested. Inhibition of BCR/ABL by imatinib or nilotinib (AMN107) led to decreased expression of the Plk1 protein in CML cells, suggesting that BCR/ABL promotes Plk1 generation. Silencing of Plk1 in CML cells by a small interfering RNA approach was followed by cell cycle arrest and apoptosis. Furthermore, the Plk1-targeting drug BI 2536 was found to inhibit proliferation of imatinib-sensitive and imatinib-resistant CML cells, including leukemic cells, carrying the T315 mutation of BCR/ABL with reasonable IC50 values (1-50 nmol/L). The growth-inhibitory effects of BI 2536 on CML cells were found to be associated with cell cycle arrest and apoptosis. Moreover, BI 2536 was found to synergize with imatinib and nilotinib in producing growth inhibition in CML cells. In conclusion, Plk1 is expressed in CML cells and may represent a novel, interesting target in imatinib-sensitive and imatinib-resistant CML. Cancer Res; 70(4); 1513-23. (C) 2010 AACR.