PLK4 is a potential therapeutic target in nonmelanoma skin cancers: Evidence from molecular and in vivo studies

Abstract

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.

Keywords: CFI‐400945; PLK4; centrinone; polo‐like kinase.