Role of Polo-Like Kinase 4 (PLK4) in Epithelial Cancers and Recent Progress in its Small Molecule Targeting for Cancer Management.
Role of Polo-Like Kinase 4 (PLK4) in Epithelial Cancers and Recent Progress in its Small Molecule Targeting for Cancer Management.
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DOI：
10.1158/1535-7163.mct-20-0741
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发表时间：
2021-04
影响因子：
5.7
通讯作者：
Ahmad N
中科院分区：
文献类型：
--
作者：
Garvey DR;Chhabra G;Ndiaye MA;Ahmad N
polo 样激酶 (PLK) 是传统上与细胞周期调节相关的丝氨酸/苏氨酸激酶家族。该家族结构独特的成员 PLK4，已被证明可以通过与多种中心体蛋白的相互作用来调节细胞周期中的中心粒复制。最近的研究结果表明，PLK4 在各种人类癌症中过度表达，并与癌症预后不良相关。尽管多项研究表明 PLK4 抑制可能导致癌细胞死亡，但其潜在机制在很大程度上尚不清楚。在这篇综述中，我们讨论了 PLK4 的结构、定位和功能，以及 PLK4 在上皮癌中的功能意义，以及一些初步工作表明 PLK4 在关键的癌症进展过程上皮-间质转化 (EMT) 中的作用。我们还基于对 PLK4 抑制剂在临床前开发和临床试验中的可用数据的批判性分析，讨论了 PLK4 作为抗癌药物开发的药物靶点的潜力。总体而言，新出现的数据表明 PLK4 在上皮癌中发挥着重要作用，应作为潜在的生物标志物和/或治疗靶点进行进一步探索。在成功的临床试验后，对现有和下一代 PLK4 抑制剂的持续详细探索可能会为新型癌症治疗方法提供新的维度。
The polo-like kinases (PLKs) are a family of serine/threonine kinases traditionally linked to cell cycle regulation. A structurally unique member of this family, PLK4, has been shown to regulate centriole duplication during the cell cycle via interactions with a variety of centrosomal proteins. Recent findings suggest that PLK4 is overexpressed in various human cancers and associated with poor cancer prognosis. Although several studies have shown that PLK4 inhibition may lead to cancer cell death, the underlying mechanisms are largely unknown. In this review, we discuss the structure, localization and function of PLK4, along with the functional significance of PLK4 in epithelial cancers and some preliminary work suggesting a role for PLK4 in the key cancer progression process epithelial-mesenchymal transition (EMT). We also discuss the potential of PLK4 as a druggable target for anti-cancer drug development based on critical analysis of the available data of PLK4 inhibitors in pre-clinical development and clinical trials. Overall, the emerging data suggests that PLK4 plays an essential role in epithelial cancers and should be further explored as a potential biomarker and/or therapeutic target. Continued detailed exploration of available and next-generation PLK4 inhibitors may provide a new dimension for novel cancer therapeutics following successful clinical trials.