MELK作为肺癌潜在治疗靶点的研究及其抑制剂筛选

在全球范围内，肺癌已成为发病率和死亡率增长最快的恶性肿瘤之一，严重威胁着人类的健康。在我国，肺癌的发病率和死亡率高居恶性肿瘤首位，且多数患者确诊时已属晚期。而化疗作为肺癌晚期治疗的主要手段，在近十年来并未有突破性进展, 且可有效用于临床治疗肺癌的靶向药物依旧稀少。因此，寻求新的肺癌治疗靶标并以此获得高效低毒的新靶向药物，依旧是一项充满挑战且极为迫切的任务。我们的生物信息学分析和实验数据显示MELK在肺癌中高表达，并与患者的低生存率密切相关；过表达MELK促进肿瘤细胞增殖、侵袭、转移和克隆形成。因此，我们认为MELK是肺癌潜在治疗靶点，其抑制剂是治疗肺癌的有效药物。本研究将从MELK的功能、作用机制和表观遗传调控三个方面确认MELK为肺癌潜在治疗靶点，并采用虚拟筛选结合高通量筛选模型筛选药效高、特异性强的MELK抑制剂。本课题的研究对确立MELK为肺癌药物靶点及肺癌的临床治疗具有指导意义

Lung cancer has been the fastest increasing rate of morbidity and mortality in global, threatening the human health. In china, the morbidity and mortality of lung cancer top the malignant tumor’s ranking, and most patients are diagnosed at the advanced stages. As the main therapy of advanced lung cancer, chemotherapeutics still stagnate in recently 10 years. Moreover, there are few targeted drugs applied in curing lung cancer in clinic. Thus, it is urgent to search novel target to lung cancer and design the target’s associated drugs. Our bioinformatics analyses and experimental data showed that the elevated level of MELK was observed in lung cancer patients, which was strongly correlated with reduced overall survival; overexpression of MELK also promoted the tumor cell proliferation, invasion, metastasis, and clone formation. Based on these results, we propose MELK as a potential therapeutic target of lung cancer and the application of its inhibitors could be effective drugs for the treatment of lung cancer. In this study, we will investigate the functions, mechanisms and epigenetic regulation of MELK to confirm that it is a potential therapeutic target of lung cancer. Furthermore, we will identify inhibitors targeting MELK using virtual screening followed by high throughput drug screening. It is necessary and important to identify MELK as a potential drug target and guide the treatment of lung cancer in clinic.