Role of polo like kinase 4 in melanomagenesis and melanoma progression

点击翻译按钮获取中文摘要

SUMMARY: Melanoma is one of the most aggressive human cancers with approximately 87,110 new melanoma cases and 9,730 melanoma-related deaths predicted in the U.S. in 2017. Further, melanoma is a significant problem in Veterans. The US military currently is and has been engaged, in missions all over the world, including recently, in the Middle East (Iraq and Afghanistan). Many US military personnel, who are deployed to high ultraviolet (UV) index climates in tropical and subtropical zones are potentially at a higher risk for melanoma. Further, these personnel are not adequately protected because they possibly have survival priorities other than avoiding UV exposure. Based on the Veterans Affairs Central Cancer Registry (VACCR), melanoma is among the five most frequently diagnosed cancers among VA cancer patients. Unfortunately, the available therapeutic strategies have either failed to achieve >25% response or the responses are short-lived with developing resistance to therapy. Indeed, recent advances in the understanding of melanoma biology has led to the development of targeted therapies such as BRAF inhibitors (vemurafenib and dabrafenib) achieved improvement over chemotherapy for melanomas with BRAF-mutations. However, even with these new targeted approaches, most of the patients develop resistance, thereby failing to achieve lasting tumor regression. Therefore, further research is needed to understand the mechanism of melanoma development and progression. Polo-like kinase 4 (PLK4), a serine/threonine kinase, is the master regulator of centriole duplication. PLK4 is a low abundance suicidal kinase that is known to autophosphorylate itself to promote its own destruction to limit centriole duplication once per cell cycle. Based on recent research, PLK4 is emerging as a potential target for cancer treatment. PLK4 has been suggested to be involved in certain cancers. Interestingly, overexpression of PLK4 has been shown to result in supernumerary centrosomes and loss of primary cilia in transgenic mice and gastric cancer cells. Importantly, primary cilia exist in melanocytes and frequently lost in melanoma. Although limited information is available regarding the potential role of PLK4 in certain cancers, its involvement in melanoma development and progression has not been evaluated. In our preliminary data, we have found that PLK4 is overexpressed in melanoma cells and human tissues (in a limited number of specimens studied) and its inhibition via a small molecule inhibitor centrinone B results in a significant anti-proliferative response in multiple human melanoma cell lines. Thus, based on available literature and our preliminary data, we propose to test the hypothesis that PLK4 plays a critical role in melanoma development and progression and could serve as a novel target for melanoma management. The following specific aims are proposed; 1) to define the role of PLK4 in melanoma development and progression, employing a tissue microarray (TMA) created from retrospective melanoma tissues from Veteran patients, and an in vitro cell transformation model; 2) to determine the functional and mechanistic significance of PLK4 in melanoma (downstream mechanisms and effect on cilia formation), in vitro and in vivo; 3) to determine the therapeutic significance of PLK4 in melanoma in human-relevant mouse models of melanoma, namely, Braftm1Mmcm Ptentm1Hwu Tg(Tyr-cre/ERT2)13Bos/BosJ model and patient-derived xenografts (PDX) model. This may ultimately lead to development of novel diagnostic, prognostic or therapeutic approaches for melanoma. Since melanoma incidence seems to be higher in the Veteran population and our proposed study aimed at defining the molecular mechanism of melanoma development may lead to identification of novel strategies for the management of this deadly neoplasm. Therefore, our proposed work is relevant and significant to the health care of Veterans and is in line with the mission of the Department of Veteran Affairs.