Yoshimura Takuma, Kamatani Takashi, Ookubo Aki, Takahashi Mio, Itoh Manabu, Ebisudani Toshiki, Masugi Yohei, Toyonaga Tomomi, Hamamoto Junko, Saotome Keiko, Sakai Kensuke, Yoshihama Tomoko, Moritoki Nobuko, Shibata Shinsuke, Yasuda Hiroyuki, Sato Toshiro, Sato Taka-Aki, Aoki Daisuke, Yamagami Wataru, Tsunoda Tatsuhiko, Chiyoda Tatsuyuki
Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.
JSR-Keio University Medical and Chemical Innovation Center (JKiC), Keio University School of Medicine, Tokyo, Japan.
Cancer Res Commun. 2025 Jun 1;5(6):1018-1033. doi: 10.1158/2767-9764.CRC-25-0024.
There are currently no effective treatments available for clear cell ovarian cancer (CCC). In this study, we aimed to identify effective drugs for CCC through high-throughput drug screening (HTDS) using ovarian cancer organoids and determine novel therapeutic targets based on the biological characteristics of CCC through omics analysis. An ovarian cancer organoid biobank was established, and HTDS was conducted using CCC organoids based on libraries of 361 and 4,560 compounds. The efficacy of the identified drugs was verified in in vitro and in vivo experiments using a patient-derived organoid xenograft mouse model. Transcriptome analysis was performed to identify genes related to the pathways targeted by the identified drugs in CCC and to assess their potential as therapeutic targets. Proteasome inhibitors and dinaciclib were extracted using HTDS and shown to inhibit tumorigenesis in vitro and in vivo. CCC, like multiple myeloma, exhibited activated endoplasmic reticulum (ER) stress and unfolded protein response (UPR), and treatment with proteasome inhibitors further enhanced ER stress and UPR, ultimately leading to cell death. Transcriptome analysis identified anterior gradient-2 (AGR2) as a key gene involved in UPR in CCC. CRISPR knockout of AGR2 suppressed cell proliferation, increased sensitivity to proteasome inhibitors, and reversed platinum resistance in CCC. AGR2 knockout also upregulated Schlafen 11, contributing to platinum sensitivity. ER stress and the UPR are activated in CCC, and proteasome inhibitors disrupt this balance, ultimately leading to cell death. AGR2 may serve as a potential therapeutic target in CCC.
Proteasome inhibitors and dinaciclib are identified as effective drugs for CCC. CCC has a high basal UPR, and proteasome inhibition may disrupt this balance. AGR2 is involved in the UPR of CCC, and inhibiting AGR2 further enhances the UPR and confers platinum sensitivity, making it a potential therapeutic target.
目前尚无针对透明细胞卵巢癌（CCC）的有效治疗方法。在本研究中，我们旨在通过使用卵巢癌类器官的高通量药物筛选（HTDS）来确定针对CCC的有效药物，并通过组学分析基于CCC的生物学特性确定新的治疗靶点。建立了卵巢癌类器官生物样本库，并基于361种和4560种化合物的文库，使用CCC类器官进行了HTDS。使用患者来源的类器官异种移植小鼠模型在体外和体内实验中验证了所鉴定药物的疗效。进行转录组分析以鉴定与CCC中所鉴定药物靶向的途径相关的基因，并评估它们作为治疗靶点的潜力。使用HTDS提取蛋白酶体抑制剂和地西他滨，并证明它们在体外和体内均能抑制肿瘤发生。与多发性骨髓瘤一样，CCC表现出内质网（ER）应激和未折叠蛋白反应（UPR）激活，蛋白酶体抑制剂治疗进一步增强了ER应激和UPR，最终导致细胞死亡。转录组分析确定前梯度2（AGR2）是参与CCC中UPR的关键基因。AGR2的CRISPR敲除抑制了细胞增殖，增加了对蛋白酶体抑制剂的敏感性，并逆转了CCC中的铂耐药性。AGR2敲除还上调了Slfn11，有助于铂敏感性。CCC中激活了ER应激和UPR，蛋白酶体抑制剂破坏了这种平衡，最终导致细胞死亡。AGR2可能是CCC的潜在治疗靶点。
蛋白酶体抑制剂和地西他滨被确定为CCC的有效药物。CCC具有较高的基础UPR，蛋白酶体抑制可能会破坏这种平衡。AGR2参与CCC的UPR，抑制AGR2进一步增强UPR并赋予铂敏感性，使其成为潜在的治疗靶点。
