Department of Obstetrics and Gynecology, School of Medicine, J.W. Goethe University, Frankfurt, Germany.
German Cancer Consortium (DKTK), Heidelberg, Germany.
Oncogene. 2016 Jan 14;35(2):135-47. doi: 10.1038/onc.2015.105. Epub 2015 Apr 27.
The polo-like kinases (Plks) encompass a family of five serine/threonine protein kinases that play essential roles in many cellular processes involved in the control of the cell cycle, including entry into mitosis, DNA replication and the response to different types of stress. Plk1, which has been validated as a cancer target, came into the focus of many pharmaceutical companies for the development of small-molecule inhibitors as anticancer agents. Recently, FDA (Food and Drug Administration) has granted a breakthrough therapy designation to the Plk inhibitor BI 6727 (volasertib), which provided a survival benefit for patients suffering from acute myeloid leukemia. However, the various ATP-competitive inhibitors of Plk1 that are currently in clinical development also inhibit the activities of Plk2 and Plk3, which are considered as tumor suppressors. Plk3 contributes to the control and progression of the cell cycle while acting as a mediator of apoptosis and various types of cellular stress. The aberrant expression of Plk3 was found in different types of tumors. Recent progress has improved our understanding of Plk3 in regulating stress signaling and tumorigenesis. When using ATP-competitive Plk1 inhibitors, the biological roles of Plk1-related family members like Plk3 in cancer cells need to be considered carefully to improve treatment strategies against cancer.
丝氨酸/苏氨酸蛋白激酶家族中的 Polo 样激酶（Plks）包含五个蛋白激酶，它们在控制细胞周期的许多细胞过程中发挥着重要作用，包括进入有丝分裂、DNA 复制以及对不同类型压力的反应。Plk1 已被验证为癌症靶点，许多制药公司将其作为小分子抑制剂开发的重点，以开发抗癌药物。最近，美国食品和药物管理局（FDA）授予 Plk 抑制剂 BI 6727（volasertib）突破性治疗指定，这为患有急性髓细胞白血病的患者提供了生存获益。然而，目前处于临床开发阶段的各种 ATP 竞争性 Plk1 抑制剂也抑制 Plk2 和 Plk3 的活性，Plk2 和 Plk3 被认为是肿瘤抑制因子。Plk3 有助于控制和促进细胞周期，同时作为细胞凋亡和各种类型细胞应激的介质。在不同类型的肿瘤中发现 Plk3 的异常表达。最近的进展提高了我们对 Plk3 在调节应激信号和肿瘤发生中的作用的理解。在使用 ATP 竞争性 Plk1 抑制剂时，需要仔细考虑 Plk1 相关家族成员（如 Plk3）在癌细胞中的生物学作用，以改善针对癌症的治疗策略。
