Synergism between inhibitors of Aurora A and KIF11 overcomes KIF15-dependent drug resistance
Synergism between inhibitors of Aurora A and KIF11 overcomes KIF15-dependent drug resistance
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DOI：
10.1016/j.molonc.2014.05.007
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发表时间：
2014-12-01
影响因子：
6.6
通讯作者：
Poon, Randy Y. C.
中科院分区：
文献类型：
--
作者：
Ma, Hoi Tang;Erdal, Sergio;Poon, Randy Y. C.
有丝分裂驱动蛋白KIF11（也称为Eg5）在纺锤体功能中起关键作用。尽管目前有许多KIF11的小分子抑制剂正在临床开发中，但通过另一种名为KIF15的驱动蛋白的补偿，可能会产生耐药性。使用新开发的基于红外线的细胞系统，我们发现最新一代KIF11抑制剂（SB743921）的有效性可以通过Aurora A激酶的几种抑制剂来增强。包括活细胞成像和等效线图分析在内的证据表明，靶向KIF11和Aurora A一起协同促进单星纺锤体形成和有丝分裂灾难，支持Aurora A和KIF11的中心体调节平行途径的模型。我们还开发了KIF15依赖性SB743921抗性细胞模型。值得注意的是，Aurora A抑制剂也可以克服耐药性。这些结果为提高Aurora A和KIF11抑制剂的有效性和解决耐药性问题提供了分子基础。(C)2014年欧洲生物化学学会联合会。Elsevier B.V.出版，保留所有权利。
The mitotic kinesin KIF11 (also called Eg5) plays critical roles in spindle functions. Although a number of small-molecule inhibitors of KIF11 are currently in clinical development, drug-resistance could be developed through compensation by another kinesin called KIF15. Using a newly developed infrared-based cell system, we discovered that the effectiveness of one of the latest generations of KIF11 inhibitor (SB743921) could be enhanced with several inhibitors of Aurora A kinase. Evidence including live-cell imaging and isobologram analysis indicated that targeting KIF11 and Aurora A together promoted monoastral spindle formation and mitotic catastrophe synergistically, supporting a model of parallel pathways of centrosome regulation by Aurora A and KIF11. We also developed a KIF15-dependent SB743921-resistance cell model. Significantly, the drug-resistance could also be overcome with Aurora A inhibitors. These results provide a molecular basis for increasing the effectiveness of Aurora A and KIF11 inhibitors and tackling problems of drug resistance. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.