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.

Melanoma incidences are increasing rapidly, and ultraviolet (UV) radiation from the sun is believed to be its major contributing factor. UV exposure causes DNA damage in skin which may initiate cutaneous skin cancers including melanoma. Melanoma arises from melanocytes, the melanin-producing skin cells, following genetic dysregulations resulting into hyperproliferative phenotype and neoplastic transformation. Both UVA and UVB exposures to the skin are believed to trigger melanocytic hyperplasia and melanomagenesis. Melanocytes by themselves are deficient in repair of oxidative DNA damage and UV-induced photoproducts. Nicotinamide, an active form of vitamin B3 and a critical component of the human body's defense system has been shown to prevent certain cancers including nonmelanoma skin cancers. However, the mechanism of nicotinamide's protective effects is not well understood. Here, we investigated potential protective effects and mechanism of nicotinamide against UVA- and/or UVB- induced damage in normal human epidermal melanocytes. Our data demonstrated an appreciable protective effect of nicotinamide against UVA- and/or UVB- induced DNA damage in melanocytes by decreasing both cyclobutane pyrimidine dimers and 8-hydroxy-2'-deoxyguanosine levels. We found that the photoprotective response of nicotinamide was associated with the activation of nucleotide excision repair genes and NRF2 signaling. Further studies are needed to validate our findings in in vivo models.

Background Identification of novel molecular target(s) is important for designing newer mechanistically driven approaches for the treatment of prostate cancer (PCa), which is one of the main causes of morbidity and mortality in men. In this study, we determined the role of polo‐like kinase 4 (PLK4), which regulates centriole duplication and centrosome amplification (CA), in PCa. Materials and Methods Employing human PCa tissue microarrays, we assessed the prevalence of CA, correlated with Gleason score, and estimated major causes of CA in PCa (cell doubling vs. centriole overduplication) by staining for mother/mature centrioles. We also assessed PLK4 expression and correlated it with CA in human PCa tissues and cell lines. Further, we determined the effects of PLK4 inhibition in human PCa cells. Results Compared to benign prostate, human PCa demonstrated significantly higher CA, which was also positively correlated with the Gleason score. Further, most cases of CA were found to arise by centriole overduplication rather than cell doubling events (e.g., cytokinesis failure) in PCa. In addition, PLK4 was overexpressed in human PCa cell lines and tumors. Moreover, PLK4 inhibitors CFI‐400945 and centrinone‐B inhibited cell growth, viability, and colony formation of both androgen‐responsive and androgen‐independent PCa cell lines. PLK4 inhibition also induced cell cycle arrest and senescence in human PCa cells. Conclusions CA is prevalent in PCa and arises predominantly by centriole overduplication as opposed to cell doubling events. Loss of centrioles is cellular stress that can promote senescence and suggests that PLK4 inhibition may be a viable therapeutic strategy in PCa.

Nonmelanoma skin cancers (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are the most common malignancies in the United States, with over 5.4 million cases treated in more than 3.3 million people each year. The existing preventive and therapeutic strategies have not been fully effective in NMSC management. Therefore, an enhanced knowledge of the molecular mechanisms of NMSC may provide novel targets for prevention and treatment of these cancers. This study was undertaken to determine the potential role of the serine/threonine kinase, polo-like kinase 4 (PLK4) in NMSC. PLK4 plays an important role in cell division by regulating centriole duplication during the cell cycle. Essentially, PLK4 is a low abundance suicidal kinase capable of auto-phosphorylating itself to cause its own destruction to limit centriole duplication once per cell cycle phase. Since centrosome aberrations are frequently seen in cancer, the central role of PLK4 in centriole duplication suggests its significance as a potential target for cancer management. In this study, employing in vitro and ex vivo approaches, we tested the hypothesis that PLK4 is differentially expressed in NMSC and may be used as a potential new target for the management of these neoplasms. Employing real time quantitative polymerase chain reaction as well as immunoblot analyses, we found that compared to normal human epidermal keratinocytes (NHEKs), PLK4 was significantly overexpressed in human epidermoid carcinoma A431 cells and basal cell carcinoma UW-BCC1 cell lines at both mRNA and protein levels. Further, we determined the expression profile of PLK4 in NMSC using immunohistochemical analysis of multiple tissue microarrays containing cores of normal skin, BCC and SCC. Our data demonstrated a marked overexpression of PLK4 in cancerous tissues, compared to normal skin. To further assess the role of PLK4 overexpression in NMSC, we determined the effects of small molecule inhibitors of PLK4, centrinone-B and CFI-400945 in vitro. We found that treatment with centrinone-B or CFI-400945 resulted in dose- as well as time-dependent decreases in the growth and viability. Further, centrinone-B and CFI-400945 treatments also resulted in a marked reduction in the clonogenic survival of skin cancer cells. Taken together, our study suggests that PLK4 has a pro-proliferative function in NMSC. Additional detailed studies are ongoing in our laboratory to determine the functional significance of PLK4 in NMSC. Based on our data, we suggest that PLK4 should be further evaluated as a potential target and prognostic biomarker for the management of NMSC. Citation Format: Debra R. Garvey, Mary A. Ndiaye, Chandra K. Singh, Ambria Noll, Nihal Ahmad. The potential role of polo-like kinase 4 in non-melanoma skin cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 547.

Isotretinoin is the gold standard treatment for moderate to severe acne but its use is limited by its side effect profile. We need to accelerate drug discovery for moderate to severe acne. Drug-repurposing is one approach to accelerating drug discovery and those drugs that elicit a similar "signature" to isotretinoin may be beneficial as acne therapies. In order to generate "isotretinoin's signature", a complete understanding of the mechanisms by which isotretinoin improves acne in human patients is required. Using a multi-omics approach, we performed a comprehensive study to investigate the effects of isotretinoin in whole skin, whole blood and the facial skin microbiome in 18 acne patients before, during and after isotretinoin therapy. Acne severity and lesion counts, sebum measurements and clinical response were documented at each study visit. RNA-Sequencing was performed cell lines and whole skin and blood samples from patients. The serum chemokine and cytokine profiles were determined by multiplex ELISA assays. The follicular skin microbiome was sampled by cyanoacrylate follicular biopsy and subjected to whole genome shot-gun sequencing. Parallel in vitro experiments using human SEB-1 sebocytes, keratinocytes and fibroblasts exposed to isotretinoin were done to determine the skin cell-specific effects of isotretinoin. Our data sets allow for the development of a network model of isotretinoin effects that can be used to test existing drugs and novel compounds for desired effects in acne treatment.