文章：

polo样激酶和极光激酶在癌症中的共享和分离功能

Shared and separate functions of polo-like kinases and aurora kinases in cancer

原文发布日期：2010-11-24

DOI: 10.1038/nrc2964

类型: Review Article

开放获取: 否

要点：

1. The polo-like kinases 1–5 (PLK1–5), and aurora kinases, aurora kinase A, aurora kinase B and aurora kinase C have essential roles during cell division, and a large number of inhibitors for these kinases are currently being evaluated as anticancer drugs in Phase I and Phase II clinical trials.
2. Information on the selectivity of these compounds in vivo is limited, but it is likely that off-target effects within the same kinase families will affect efficacy and toxicity profiles.
3. The efficacy of polo-like kinase and aurora kinase inhibitors probably primarily depends on their capacity to severely disrupt normal cell division, implying a limited tumour specificity of these types of drugs.
4. It is unclear whether PLK1 and the aurora kinases have oncogenic or tumour suppressor activity when deregulated. However, the increased cancer incidence in heterozygous mice suggests a role for them as tumour suppressors, probably through the prevention of chromosome instability.
5. PLK1 and the aurora kinases co-regulate multiple processes in the dividing cell, such as entry into mitosis, mitotic spindle formation, sister chromatid resolution, chromosome–spindle connections and cytokinesis. Although some overlap in clinical performance can be expected of PLK1 and aurora kinase inhibitors, these kinases can also antagonize one another. Consequently, the outcome of selective PLK1, aurora kinase A or aurora kinase B inhibition, compared with combined inhibition, will certainly be different.
6. Several treatment approaches have been proposed, which consist of PLK1, aurora kinase A or aurora kinase B inhibition combined with conventional chemotherapeutic agents that might enhance the efficacy and specificity of these drugs.

要点翻译：

1. Polo样激酶1-5（PLK1-5）和极光激酶（包括极光激酶A、B和C）在细胞分裂过程中具有关键作用。目前有大量针对这些激酶的抑制剂作为抗癌药物正处于I期和II期临床试验阶段。
2. 关于这些化合物在体内选择性的信息有限，但同一激酶家族内的脱靶效应很可能会影响其疗效和毒性特征。
3. Polo样激酶和极光激酶抑制剂的疗效可能主要取决于其严重破坏正常细胞分裂的能力，这意味着此类药物的肿瘤特异性较为有限。
4. 目前尚不清楚PLK1和极光激酶在失调时是否具有促癌或抑癌活性。然而，杂合子小鼠癌症发病率升高提示它们可能通过预防染色体不稳定性而发挥抑癌作用。
5. PLK1与极光激酶共同调控分裂细胞的多个过程，例如进入有丝分裂、有丝分裂纺锤体形成、姐妹染色单体分离、染色体-纺锤体连接和胞质分裂。虽然PLK1与极光激酶抑制剂在临床疗效上可能存在部分重叠，但这些激酶之间也可能相互拮抗。因此，选择性抑制PLK1、极光激酶A或极光激酶B与联合抑制的结果必然存在差异。
6. 目前已有多种治疗策略被提出，包括将PLK1、极光激酶A或极光激酶B抑制剂与常规化疗药物联用，这可能增强此类药物的疗效和特异性。

英文摘要：

Large numbers of inhibitors for polo-like kinases and aurora kinases are currently being evaluated as anticancer drugs. Interest in these drugs is fuelled by the idea that these kinases have unique functions in mitosis. Within the polo-like kinase family, the emphasis for targeted therapies has been on polo-like kinase 1 (PLK1), and in the aurora kinase family drugs have been developed to specifically target aurora kinase A (AURKA; also known as STK6) and/or aurora kinase B (AURKB; also known as STK12). Information on the selectivity of these compounds in vivo is limited, but it is likely that off-target effects within the same kinase families will affect efficacy and toxicity profiles. In addition, it is becoming clear that interplay between polo-like kinases and aurora kinases is much more extensive than initially anticipated, and that both kinase families are important factors in the response to classical chemotherapeutics that damage the genome or the mitotic spindle. In this Review we discuss the implications of these novel insights on the clinical applicability of polo-like kinase and aurora kinase inhibitors.

摘要翻译： 

大量polo样激酶（PLK）和极光激酶（Aurora kinase）抑制剂正被作为抗癌药物进行评估。人们之所以对这些药物感兴趣，是因为这些激酶在有丝分裂中具有独特功能。在polo样激酶家族中，治疗靶点的重点集中在polo样激酶1（PLK1）；而在极光激酶家族中，药物开发则特异性地针对极光激酶A（AURKA，又称STK6）和/或极光激酶B（AURKB，又称STK12）。这些化合物在体内的选择性信息有限，但很可能同一激酶家族内的脱靶效应会影响其疗效和毒性特征。此外，越来越多的证据表明，polo样激酶与极光激酶之间的相互作用远比最初预期的广泛，并且这两个激酶家族都是细胞对损伤基因组或有丝分裂纺锤体的经典化疗药物产生应答的重要因素。在本综述中，我们探讨这些新见解对polo样激酶和极光激酶抑制剂临床适用性的影响。

原文链接：

Shared and separate functions of polo-like kinases and aurora kinases in cancer