Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA; GW Cancer Center, The George Washington University, Washington, DC, 20052, USA.
Department of Obstetrics and Gynecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Cancer Lett. 2018 Aug 1;428:104-116. doi: 10.1016/j.canlet.2018.04.029. Epub 2018 Apr 26.
The acquisition of resistance is a major obstacle to the clinical use of platinum drugs for ovarian cancer treatment. Increase of DNA damage response is one of major mechanisms contributing to platinum-resistance. However, how DNA damage response is regulated in platinum-resistant ovarian cancer cells remains unclear. Using quantitative high throughput combinational screen (qHTCS) and RNA-sequencing (RNA-seq), we show that dual oxidase maturation factor 1 (DUOXA1) is overexpressed in platinum-resistant ovarian cancer cells, resulting in over production of reactive oxygen species (ROS). Elevated ROS level sustains the activation of ATR-Chk1 pathway, leading to resistance to cisplatin in ovarian cancer cells. Moreover, using qHTCS we identified two Chk1 inhibitors (PF-477736 and AZD7762) that re-sensitize resistant cells to cisplatin. Blocking this novel pathway by inhibiting ROS, DUOXA1, ATR or Chk1 effectively overcomes cisplatin resistance in vitro and in vivo. Significantly, the clinical studies also confirm the activation of ATR and DOUXA1 in ovarian cancer patients, and elevated DOUXA1 or ATR-Chk1 pathway correlates with poor prognosis. Taken together, our findings not only reveal a novel mechanism regulating cisplatin resistance, but also provide multiple combinational strategies to overcome platinum-resistance in ovarian cancer.
获得耐药性是临床应用铂类药物治疗卵巢癌的主要障碍。增加 DNA 损伤反应是导致铂耐药的主要机制之一。然而，DNA 损伤反应如何在铂耐药卵巢癌细胞中被调控仍不清楚。通过定量高通量组合筛选（qHTCS）和 RNA 测序（RNA-seq），我们发现双氧化酶成熟因子 1（DUOXA1）在铂耐药卵巢癌细胞中过表达，导致活性氧（ROS）过度产生。升高的 ROS 水平维持 ATR-Chk1 通路的激活，导致卵巢癌细胞对顺铂的耐药性。此外，我们通过 qHTCS 鉴定了两种 Chk1 抑制剂（PF-477736 和 AZD7762），它们使耐药细胞对顺铂重新敏感。通过抑制 ROS、DUOXA1、ATR 或 Chk1 阻断这条新途径，可有效克服铂耐药性在体外和体内。值得注意的是，临床研究还证实了 ATR 和 DOUXA1 在卵巢癌患者中的激活，并且 DOUXA1 或 ATR-Chk1 通路的升高与预后不良相关。总之，我们的研究结果不仅揭示了调控顺铂耐药性的新机制，还为克服卵巢癌铂耐药性提供了多种联合策略。
