卵巢黏液性囊腺癌（OCCC）对铂基标准治疗方法效果不佳。OCCC是一种特殊亚型的卵巢上皮癌。在东亚（日本、韩国、中国、新加坡）OCCC占卵巢癌的25％，在欧洲和北美为6-10％。该癌多由ARID1A的频繁失活所导致，10％的子宫内膜异位症患者会恶化为OCCC。本研究旨在寻找治疗OCCC的FDA批准或临床试验药物。通过高通量筛选166种FDA批准、正在临床试验或在临床前研究的化合物，确定了几种针对OCCC的细胞毒性化合物。ARID1A敲除的细胞对mTOR抑制剂（PP242）、双重mTOR/PI3K抑制剂（GDC0941）、ATR抑制剂（AZD6738）或MDM2抑制剂（RG7388）的抑制作用较对照组更为敏感。同时，针对BH3结构域（AZD4320）和SRC（AZD0530）的化合物优先对ARID1A突变的细胞株具有细胞毒性。此外，WEE1抑制剂（AZD1775）对OCCC细胞系表现出广泛的细胞毒性，不受ARID1A状态影响。在166种化合物中，我们发现ATR和WEE1的抑制剂对一组OCCC细胞系具有细胞毒性。这两种药物已经处于其他临床试验中，是治疗OCCC的理想药物。© 2023. The Author(s).

Standard platinum-based therapy for ovarian cancer is inefficient against ovarian clear cell carcinoma (OCCC). OCCC is a distinct subtype of epithelial ovarian cancer. OCCC constitutes 25% of ovarian cancers in East Asia (Japan, Korea, China, Singapore) and 6-10% in Europe and North America. The cancer is characterized by frequent inactivation of ARID1A and 10% of cases of endometriosis progression to OCCC. The aim of this study was to identify drugs that are either FDA-approved or in clinical trials for the treatment of OCCC.High throughput screening of 166 compounds that are either FDA-approved, in clinical trials or are in pre-clinical studies identified several cytotoxic compounds against OCCC. ARID1A knockdown cells were more sensitive to inhibitors of either mTOR (PP242), dual mTOR/PI3K (GDC0941), ATR (AZD6738) or MDM2 (RG7388) compared to control cells. Also, compounds targeting BH3 domain (AZD4320) and SRC (AZD0530) displayed preferential cytotoxicity against ARID1A mutant cell lines. In addition, WEE1 inhibitor (AZD1775) showed broad cytotoxicity toward OCCC cell lines, irrespective of ARID1A status.In a selection of 166 compounds we showed that inhibitors of ATR and WEE1 were cytotoxic against a panel of OCCC cell lines. These two drugs are already in other clinical trials, making them ideal candidates for treatment of OCCC.© 2023. The Author(s).