Treatment for ovarian clear cell carcinoma with combined inhibition of WEE1 and ATR.
Treatment for ovarian clear cell carcinoma with combined inhibition of WEE1 and ATR.
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DOI：
10.1186/s13048-023-01160-y
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发表时间：
2023-04-22
影响因子：
4
通讯作者：
Koeffler, H. Phillip
中科院分区：
文献类型：
--
作者：
Chien, Wenwen;Tyner, Jeffrey W. W.;Gery, Sigal;Zheng, Yueyuan;Li, Li-Yan;Pillai, Mohan Shankar Gopinatha;Nam, Chehyun;Bhowmick, Neil A. A.;Lin, De-Chen;Koeffler, H. Phillip
卵巢癌的标准铂类疗法对卵巢透明细胞癌 (OCCC) 无效。 OCCC 是上皮性卵巢癌的一种独特亚型。 OCCC 在东亚（日本、韩国、中国、新加坡）占卵巢癌的 25%，在欧洲和北美占 6-10%。这种癌症的特点是 ARID1A 频繁失活，10% 的子宫内膜异位症病例进展为 OCCC。本研究的目的是确定 FDA 批准的或正在进行临床试验的用于治疗 OCCC 的药物。对 166 种经 FDA 批准、正在进行临床试验或正在进行临床前研究的化合物进行高通量筛选，鉴定出几种针对 OCCC 的细胞毒性化合物。与对照细胞相比，ARID1A 敲低细胞对 mTOR (PP242)、双 mTOR/PI3K (GDC0941)、ATR (AZD6738) 或 MDM2 (RG7388) 抑制剂更敏感。此外，靶向 BH3 结构域 (AZD4320) 和 SRC (AZD0530) 的化合物对 ARID1A 突变细胞系表现出优先的细胞毒性。此外，无论 ARID1A 状态如何，WEE1 抑制剂 (AZD1775) 对 OCCC 细胞系均表现出广泛的细胞毒性。在精选的 166 种化合物中，我们证明 ATR 和 WEE1 抑制剂对一组 OCCC 细胞系具有细胞毒性。这两种药物已经进入其他临床试验，使其成为治疗 OCCC 的理想候选药物。在线版本包含可在 10.1186/s13048-023-01160-y 获取的补充材料。
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. The online version contains supplementary material available at 10.1186/s13048-023-01160-y.
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影响因子：
8
作者：
Berns K;Caumanns JJ;Hijmans EM;Gennissen AMC;Severson TM;Evers B;Wisman GBA;Jan Meersma G;Lieftink C;Beijersbergen RL;Itamochi H;van der Zee AGJ;de Jong S;Bernards R
通讯作者：
Bernards R
影响因子：
3.7
作者：
Yoon H;Choi YL;Song JY;Do I;Kang SY;Ko YH;Song S;Kim BG
通讯作者：
Kim BG
DOI：
10.1074/mcp.m116.062539
发表时间：
2016-11
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Goldman AR;Bitler BG;Schug Z;Conejo-Garcia JR;Zhang R;Speicher DW
通讯作者：
Speicher DW
DOI：
10.1158/1078-0432.ccr-15-0479
发表时间：
2015-11-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Karnitz LM;Zou L
通讯作者：
Zou L
影响因子：
4.7
作者：
Fejzo, Marlena S.;Chen, Hsiao-Wang;Slamon, Dennis J.
通讯作者：
Slamon, Dennis J.