Inhibition of Aurora kinase B is important for biologic activity of the dual inhibitors of BCR-ABL and Aurora kinases R763/AS703569 and PHA-739358 in BCR-ABL transformed cells.
Inhibition of Aurora kinase B is important for biologic activity of the dual inhibitors of BCR-ABL and Aurora kinases R763/AS703569 and PHA-739358 in BCR-ABL transformed cells.
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DOI：
10.1371/journal.pone.0112318
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
von Bubnoff N
中科院分区：
文献类型：
--
作者：
Illert AL;Seitz AK;Rummelt C;Kreutmair S;Engh RA;Goodstal S;Peschel C;Duyster J;von Bubnoff N
ABL酪氨酸激酶抑制剂（TKI）如伊马替尼、达沙替尼和尼洛替尼是CML常规治疗的金标准。然而，耐药性的出现仍然是一个主要问题。ABL tki耐药CML的替代治疗策略是迫切需要的。我们询问双重抑制BCR-ABL和Aurora激酶A-C是否可以克服ABL激酶突变介导的耐药。因此，我们在异位表达野生型（wt）或tki耐药BCR-ABL突变体的Ba/F3-细胞中测试了双ABL和极光激酶抑制剂pa -739358和R763/AS703569。我们发现这两种化合物在ABL TKI抗性细胞系中表现出很强的抗增殖和促凋亡活性，包括表达强抗性T315I突变的细胞。细胞周期分析表明，多倍体化是在没有极光激酶抑制细胞分裂的情况下持续细胞周期进展的结果。对Aurora B耐药变体的实验表明，PHA-739358同时作用于BCR-ABL和Aurora激酶B，而对Aurora激酶B的抑制可能足以抑制R763/AS703569所观察到的抗增殖活性。综上所述，我们的数据表明，双重ABL和极光激酶抑制可能用于克服ABL TKI耐药CML。
ABL tyrosine kinase inhibitors (TKI) like Imatinib, Dasatinib and Nilotinib are the gold standard in conventional treatment of CML. However, the emergence of resistance remains a major problem. Alternative therapeutic strategies of ABL TKI-resistant CML are urgently needed. We asked whether dual inhibition of BCR-ABL and Aurora kinases A-C could overcome resistance mediated by ABL kinase mutations. We therefore tested the dual ABL and Aurora kinase inhibitors PHA-739358 and R763/AS703569 in Ba/F3- cells ectopically expressing wild type (wt) or TKI-resistant BCR-ABL mutants. We show that both compounds exhibited strong anti-proliferative and pro-apoptotic activity in ABL TKI resistant cell lines including cells expressing the strongly resistant T315I mutation. Cell cycle analysis indicated polyploidisation, a consequence of continued cell cycle progression in the absence of cell division by Aurora kinase inhibition. Experiments using drug resistant variants of Aurora B indicated that PHA-739358 acts on both, BCR-ABL and Aurora Kinase B, whereas Aurora kinase B inhibition might be sufficient for the anti-proliferative activity observed with R763/AS703569. Taken together, our data demonstrate that dual ABL and Aurora kinase inhibition might be used to overcome ABL TKI resistant CML.
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影响因子：
5.7
作者：
Dar AA;Goff LW;Majid S;Berlin J;El-Rifai W
通讯作者：
El-Rifai W
影响因子：
5.7
作者：
Carpinelli, Patrizia;Ceruti, Roberta;Moll, Jurgen
通讯作者：
Moll, Jurgen
影响因子：
4.8
作者：
Benten, Daniel;Keller, Gunhild;Brummendorf, Tim H.
通讯作者：
Brummendorf, Tim H.
影响因子：
20.3
作者：
Branford, Susan;Melo, Junia V.;Hughes, Timothy P.
通讯作者：
Hughes, Timothy P.
Aurora激酶A抑制作用导致p53缺陷癌细胞的p73依赖性凋亡。
影响因子：
11.2
作者：
Dar, Altaf A.;Belkhiri, Abbes;Ecsedy, Jeffrey;Zaika, Alexander;El-Rifai, Wael
通讯作者：
El-Rifai, Wael