Ndiaye Mary A, Garvey Debra R, Chhabra Gagan, Singh Chandra K, Nihal Minakshi, Ahmad Nihal
Department of Dermatology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
William S. Middleton VA Medical Center, Madison, Wisconsin, USA.
Photochem Photobiol. 2025 Jun 16. doi: 10.1111/php.70006.
Nonmelanoma skin cancers (NMSC), consisting primarily of cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC), are the most prevalent cancers in the United States and have been associated with exposure to solar ultraviolet (UV) radiation. While a majority of NMSC are surgically resectable, the inoperable or metastatic tumors need intense therapies, including targeted and immunotherapies. However, novel targeted therapies are needed to improve treatment efficacy, reduce side effects, and limit recurrence, metastasis, and drug resistance. Polo-like kinase 4 (PLK4), a member of a serine/threonine family of kinases, is being investigated as a target for anticancer drug development. However, its role in NMSC is not established. In this study, we found PLK4 to be significantly overexpressed in BCC and cSCC cells and tissues. Further, small molecule inhibition of PLK4 activity with centrinone, a specific and reversible inhibitor, and CFI-400945, an ATP-competitive inhibitor, decreased cell viability, proliferation, and clonogenic survival of human cSCC and BCC cells. Furthermore, PLK4 inhibition induced significant cell cycle arrest and apoptosis as well as modulation of key cell cycle genes as determined using a PCR Array. Additionally, CRISPR/Cas9-mediated knockdown of PLK4 in the A431 cSCC cell line showed (i) significant growth inhibitory effects in vitro, along with significant modulation in key cancer-related genes via PCR array and (ii) significantly reduced tumorigenesis in vivo in a mouse xenograft model. Overall, this study suggested that PLK4 is a potential therapeutic target and a biomarker for NMSC management. However, additional studies are needed to validate and expand these findings in additional model systems.
非黑色素瘤皮肤癌（NMSC）主要由皮肤鳞状细胞癌（cSCC）和基底细胞癌（BCC）组成，是美国最常见的癌症，并且与暴露于太阳紫外线（UV）辐射有关。虽然大多数NMSC可以通过手术切除，但无法手术切除或转移性肿瘤需要强化治疗，包括靶向治疗和免疫治疗。然而，需要新型靶向治疗来提高治疗效果、减少副作用并限制复发、转移和耐药性。Polo样激酶4（PLK4）是丝氨酸/苏氨酸激酶家族的成员，正在作为抗癌药物开发的靶点进行研究。然而，其在NMSC中的作用尚未明确。在本研究中，我们发现PLK4在BCC和cSCC细胞及组织中显著过表达。此外，使用特异性可逆抑制剂centrinone和ATP竞争性抑制剂CFI-400945对PLK4活性进行小分子抑制，可降低人cSCC和BCC细胞的细胞活力、增殖和克隆形成存活率。此外，PLK4抑制诱导了显著的细胞周期停滞和凋亡，以及使用PCR阵列测定的关键细胞周期基因的调节。此外，在A431 cSCC细胞系中，CRISPR/Cas9介导的PLK4敲低显示：（i）在体外具有显著的生长抑制作用，同时通过PCR阵列对关键癌症相关基因有显著调节；（ii）在小鼠异种移植模型中，体内肿瘤发生显著减少。总体而言，本研究表明PLK4是NMSC管理的潜在治疗靶点和生物标志物。然而，需要更多研究在其他模型系统中验证和扩展这些发现。
