联合抑制 WEE1 和 ATR 治疗卵巢透明细胞癌。
Treatment for ovarian clear cell carcinoma with combined inhibition of WEE1 and ATR.
机构信息
Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, 90048, USA.
Knight Cancer Institute, Oregon Health & Science University, Oregon Health and Science University, 2720 S.W. Moody Avenue, Portland, OR, 97201, USA.
出版信息
J Ovarian Res. 2023 Apr 22;16(1):80. doi: 10.1186/s13048-023-01160-y.
BACKGROUND
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.
RESULTS
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.
CONCLUSIONS
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.
背景
卵巢癌的标准铂类治疗对卵巢透明细胞癌（OCCC）无效。OCCC 是上皮性卵巢癌的一个独特亚型。OCCC 占东亚（日本、韩国、中国、新加坡）卵巢癌的 25%，占欧洲和北美的 6-10%。这种癌症的特征是 ARID1A 频繁失活，10%的子宫内膜异位症进展为 OCCC。本研究旨在确定用于治疗 OCCC 的已获 FDA 批准或正在临床试验中的药物。
结果
对 166 种已获 FDA 批准、处于临床试验或处于临床前研究阶段的化合物进行高通量筛选，发现了几种针对 OCCC 的细胞毒性化合物。与对照细胞相比，ARID1A 敲低细胞对 mTOR 抑制剂（PP242）、双重 mTOR/PI3K 抑制剂（GDC0941）、ATR 抑制剂（AZD6738）或 MDM2 抑制剂（RG7388）更为敏感。此外，针对 BH3 结构域的化合物（AZD4320）和 SRC 抑制剂（AZD0530）对 ARID1A 突变细胞系表现出优先的细胞毒性。此外，WEE1 抑制剂（AZD1775）对 OCCC 细胞系表现出广泛的细胞毒性，而与 ARID1A 状态无关。
结论
在 166 种化合物的选择中，我们表明ATR 和 WEE1 的抑制剂对一系列 OCCC 细胞系具有细胞毒性。这两种药物已经在其他临床试验中使用，使其成为治疗 OCCC 的理想候选药物。
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