Evolution of resistance to Aurora kinase B inhibitors in leukaemia cells.
Evolution of resistance to Aurora kinase B inhibitors in leukaemia cells.
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DOI：
10.1371/journal.pone.0030734
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kavallaris M
中科院分区：
文献类型：
--
作者：
Failes TW;Mitic G;Abdel-Halim H;Po'uha ST;Liu M;Hibbs DE;Kavallaris M
极光激酶抑制剂是目前正在临床试验中用于治疗血液系统和实体恶性肿瘤的新型有丝分裂靶向药物。然而，对影响敏感性和耐药性的分子因素的了解仍然有限。在此，我们开发并表征了对Aurora B抑制剂ZM 447439具有抗性的体外白血病模型。选择人T细胞急性淋巴细胞白血病细胞（CCRF-CEM）对4 µM ZM 447439的耐药性。CEM/AKB 4细胞对微管蛋白靶向和DNA损伤剂没有交叉耐药性，但对Aurora激酶A抑制剂过敏。测序显示极光B激酶结构域中的突变对应于G160 E氨基酸取代。在含有该突变的Aurora B中药物结合的分子建模表明，抗性是由谷氨酸取代介导的，从而阻止活性药物结合基序的形成。在更高度选择的CEM/AKB 8和CEM/AKB 16细胞中，分别在8和16 μM ZM 447439中从CEM/AKB 4依次衍生的抗性进展由额外的缺陷介导。这些缺陷独立于极光B和多药耐药途径，并且与细胞凋亡减少有关，这很可能是由于在药物存在下极光激酶B的催化活性抑制减少。我们的发现对于在白血病治疗方案中使用这些新靶向药物非常重要，并表明对治疗的耐药性可能通过多种独立机制产生。
Aurora kinase inhibitors are new mitosis-targeting drugs currently in clinical trials for the treatment of haematological and solid malignancies. However, knowledge of the molecular factors that influence sensitivity and resistance remains limited. Herein, we developed and characterised an in vitro leukaemia model of resistance to the Aurora B inhibitor ZM447439. Human T-cell acute lymphoblastic leukaemia cells, CCRF-CEM, were selected for resistance in 4 µM ZM447439. CEM/AKB4 cells showed no cross-resistance to tubulin-targeted and DNA-damaging agents, but were hypersensitive to an Aurora kinase A inhibitor. Sequencing revealed a mutation in the Aurora B kinase domain corresponding to a G160E amino acid substitution. Molecular modelling of drug binding in Aurora B containing this mutation suggested that resistance is mediated by the glutamate substitution preventing formation of an active drug-binding motif. Progression of resistance in the more highly selected CEM/AKB8 and CEM/AKB16 cells, derived sequentially from CEM/AKB4 in 8 and 16 µM ZM447439 respectively, was mediated by additional defects. These defects were independent of Aurora B and multi-drug resistance pathways and are associated with reduced apoptosis mostly likely due to reduced inhibition of the catalytic activity of aurora kinase B in the presence of drug. Our findings are important in the context of the use of these new targeted agents in treatment regimes against leukaemia and suggest resistance to therapy may arise through multiple independent mechanisms.
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