Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin.
Mol Cancer Ther. 2019 Jan;18(1):162-172. doi: 10.1158/1535-7163.MCT-17-1050. Epub 2018 Oct 10.
For mucinous ovarian cancer (MOC), standard platinum-based therapy is largely ineffective. We sought to identify possible mechanisms of oxaliplatin resistance of MOC and develop strategies to overcome this resistance. A kinome-based siRNA library screen was carried out using human MOC cells to identify novel targets to enhance the efficacy of chemotherapy. and validations of antitumor effects were performed using mouse MOC models. Specifically, the role of /PACT in oxaliplatin resistance was interrogated. We focused on , a known activator of PKR kinase, and its encoded protein PACT because it was one of the five most significantly downregulated genes in the siRNA screen. In orthotopic mouse models of MOC, we observed a significant antitumor effect of siRNA plus oxaliplatin. In addition, expression of miR-515-3p was regulated by PACT-Dicer interaction, and miR-515-3p increased the sensitivity of MOC to oxaliplatin. Mechanistically, miR-515-3p regulated chemosensitivity, in part, by targeting AXL. The /PACT axis represents an important therapeutic target in MOC to enhance sensitivity to oxaliplatin.
对于黏液性卵巢癌（MOC），标准的铂类治疗方法基本上无效。我们试图确定 MOC 对奥沙利铂耐药的可能机制，并开发克服这种耐药性的策略。使用人 MOC 细胞进行基于激酶组的 siRNA 文库筛选，以鉴定增强化疗效果的新靶标。使用小鼠 MOC 模型进行抗肿瘤作用的验证。具体来说，研究了 /PACT 在奥沙利铂耐药中的作用。我们专注于一种已知的 PKR 激酶激活剂及其编码蛋白 PACT，因为它是 siRNA 筛选中下调最明显的五个基因之一。在 MOC 的原位小鼠模型中，我们观察到 siRNA 加奥沙利铂的显著抗肿瘤作用。此外，miR-515-3p 的表达受 PACT-Dicer 相互作用调节，miR-515-3p 增加了 MOC 对奥沙利铂的敏感性。从机制上讲，miR-515-3p 通过靶向 AXL 部分调节化疗敏感性。/PACT 轴代表 MOC 中增强对奥沙利铂敏感性的重要治疗靶标。
