Jaiswal Tanya, Muntaqua Durdana, Ahmad Nihal
Department of Dermatology, University of Wisconsin, Madison, WI 53705, USA.
William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA.
Cells. 2025 Sep 4;14(17):1381. doi: 10.3390/cells14171381.
Skin cancer remains a significant global health challenge, with rising incidence and associated mortality in late-stage and drug-resistant cases. This underscores a continuing need for more effective novel therapeutic options that can be utilized for efficient management of skin cancers. A promising approach involves exploiting novel targets, which are dysregulated in skin cancer, either alone or in combination with existing therapeutics. Among these, polo-like kinases (PLKs), a family of serine/threonine kinases, has emerged as promising candidates due to their essential role in cell cycle and maintaining genomic stability, key hallmarks of cancer. Within this family, polo-like kinase 4 (PLK4) stands out as a structurally distinct member and the master regulator of centriole duplication, ensuring this process occurs only once per cell division. Dysregulation of PLK4 can disrupt genomic integrity, contributing to tumorigenesis, thus making it a promising target for cancer management. Notably, PLK4 is frequently overexpressed in several cancers, including skin cancer, and its precise role in skin cancer is an area of current investigation. Further, several small-molecule PLK4 inhibitors such as centrinone, YLZ-F5, CFI-400945, and RP-1664 have demonstrated efficacy in targeting PLK4. Among these, CFI-400945 has advanced to clinical trials, where it has shown modest anti-cancer activity. In this review, we provide a comprehensive overview of the known functions of PLK4 in skin cancer. Additionally, we discuss potential mechanistic insights into PLK4's involvement in skin cancer progression by extrapolating evidence from studies in other cancer types including colorectal cancer, thyroid cancer, lymphomas, leukemia, etc., while identifying gaps for future research.
皮肤癌仍然是一项重大的全球健康挑战，晚期和耐药病例的发病率及相关死亡率不断上升。这凸显了持续需要更有效的新型治疗方案，以用于皮肤癌的有效管理。一种有前景的方法是利用在皮肤癌中失调的新型靶点，单独或与现有疗法联合使用。其中，polo样激酶（PLKs），一类丝氨酸/苏氨酸激酶，因其在细胞周期和维持基因组稳定性（癌症的关键特征）中的重要作用而成为有前景的候选靶点。在这个家族中，polo样激酶4（PLK4）作为结构独特的成员脱颖而出，是中心粒复制的主要调节因子，确保这一过程在每个细胞分裂中仅发生一次。PLK4失调会破坏基因组完整性，促进肿瘤发生，因此使其成为癌症治疗的一个有前景的靶点。值得注意的是，PLK4在包括皮肤癌在内的几种癌症中经常过度表达，其在皮肤癌中的精确作用是当前研究的一个领域。此外，几种小分子PLK4抑制剂，如centrinone、YLZ-F5、CFI-400945和RP-1664，已证明在靶向PLK4方面具有疗效。其中，CFI-400945已进入临床试验，并显示出适度的抗癌活性。在本综述中，我们全面概述了PLK4在皮肤癌中的已知功能。此外，我们通过推断来自其他癌症类型（包括结直肠癌、甲状腺癌、淋巴瘤、白血病等）研究的证据，讨论了PLK4参与皮肤癌进展的潜在机制见解，同时确定了未来研究的空白。
