Abstract：
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with high rates of metastasis and mortality. In vitro studies suggest that selinexor (KPT-330), an inhibitor of exportin 1, may be a targeted therapeutic option for MCC. This selective inhibitor prevents the transport of oncogenic mRNA out of the nucleus. Of note, 80% of MCC tumors are integrated with Merkel cell polyomavirus (MCPyV), and virally encoded tumor-antigens, small T (sT) and large T (LT) mRNAs may require an exportin transporter to relocate to the cytoplasm and modulate host tumor-suppressing pathways. To explore selinexor as a targeted therapy for MCC, we examine its ability to inhibit LT and sT antigen expression in vitro and its impact on the prostaglandin synthesis pathway. Protein expression was determined through immunoblotting and quantified by densitometric analysis. Statistical significance was determined with t-test. Treatment of MCPyV-infected cell lines with selinexor resulted in a significant dose-dependent downregulation of key mediators of the prostaglandin synthesis pathway. Given the role of prostaglandin synthesis pathway in MCC, our findings suggest that selinexor, alone or in combination with immunotherapy, could be a promising treatment for MCPyV-infected MCC patients who are resistant to chemotherapy and immunotherapy.
摘要：
默克尔细胞癌（MCC）是一种侵袭性神经内分泌皮肤癌，具有很高的转移率和死亡率。体外研究表明，selinexor（KPT-330），输出蛋白1的抑制剂可能是MCC的靶向治疗选择。这种选择性抑制剂阻止致癌mRNA转运出细胞核。值得注意的是，80％的MCC肿瘤与默克尔细胞多瘤病毒（MCPyV）整合，和病毒编码的肿瘤抗原，小T(sT)和大T(LT)mRNA可能需要输出蛋白转运蛋白重新定位到细胞质并调节宿主肿瘤抑制途径.探索selinexor作为MCC的靶向治疗，我们研究了其体外抑制LT和sT抗原表达的能力及其对前列腺素合成途径的影响。通过免疫印迹测定蛋白质表达并通过光密度分析定量。用t检验确定统计学显著性。用selinexor处理MCPyV感染的细胞系导致前列腺素合成途径的关键介质的显着剂量依赖性下调。鉴于前列腺素合成途径在MCC中的作用，我们的发现表明selinexor,单独或与免疫疗法联合使用，可能是对化疗和免疫疗法耐药的MCPyV感染的MCC患者的有希望的治疗方法。
