mTOR is a promising therapeutic target both in cisplatin-sensitive and cisplatin-resistant clear cell carcinoma of the ovary.
mTOR is a promising therapeutic target both in cisplatin-sensitive and cisplatin-resistant clear cell carcinoma of the ovary.
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DOI：
10.1158/1078-0432.ccr-09-0365
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发表时间：
2009-09-01
期刊：
影响因子：
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通讯作者：
Kimura T
中科院分区：
文献类型：
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作者：
Mabuchi S;Kawase C;Altomare DA;Morishige K;Sawada K;Hayashi M;Tsujimoto M;Yamoto M;Klein-Szanto AJ;Schilder RJ;Ohmichi M;Testa JR;Kimura T
卵巢透明细胞癌 (CCC) 是上皮性卵巢癌的一种独特亚型，与更常见的浆液性腺癌 (SAC) 相比，对铂类化疗的敏感性较差，预后较差。为了提高生存率，有必要开发更有效地针对 CCC 的新治疗策略。我们的结果表明 mTOR 在 CCC 中比在 SAC 中更频繁地被激活。我们的数据与卵巢 CCC 患者一线治疗的未来临床研究设计相关。此外，与顺铂敏感细胞相比，顺铂耐药的 CCC 细胞中磷酸化 mTOR 的表达增加，并且对 RAD001 的敏感性更高，这为基于顺铂的一线化疗后复发性疾病的患者提供了一种新的治疗选择。 mTOR（哺乳动物雷帕霉素靶点）在细胞增殖中发挥着核心作用，被认为是癌症治疗（包括卵巢癌）的一个有前途的靶点。本研究旨在探讨 mTOR 作为卵巢透明细胞癌 (CCC) 治疗靶点的作用，卵巢透明细胞癌被视为侵袭性、化疗耐药的组织学亚型。使用 98 个原发性卵巢癌（52 个透明细胞癌和 46 个浆液性腺癌）的组织微阵列，通过免疫组织化学评估磷酸化 mTOR 的表达。然后，使用 2 对顺铂敏感亲代细胞系（RMG1 和 KOC7C）和顺铂耐药人 CCC 细胞系（RMG1-CR 和 KOC7C-CR）在体外和体内检查 RAD001（依维莫司）抑制 mTOR 的生长抑制作用。免疫组织化学分析表明，mTOR 在 CCC 中比在浆液性腺癌中更频繁地被激活（86.6% vs 50%）。 RAD001 处理在体外和体内均显着抑制 RMG1 和 KOC7C 细胞的生长。与各自的亲代细胞相比，在顺铂耐药的 RMG1-CR 和 KOC7C-CR 细胞中观察到磷酸化 mTOR 的表达增加。顺铂耐药细胞中磷酸化 mTOR 表达的增加与 AKT 激活的增加相关。在体外和体内，RMG1-CR 和 KOC7C-CR 细胞对 RAD001 的敏感性分别高于亲本 RMG1 和 KOC7C 细胞。 mTOR 在 CCC 中经常被激活，可能成为 CCC 治疗中一个有前途的治疗靶点。此外，RAD001 抑制 mTOR 可能作为既往接受顺铂治疗的患者复发性疾病的二线治疗有效。
Clear cell carcinoma (CCC) of the ovary is a distinctive subtype of epithelial ovarian cancer associated with a poorer sensitivity to platinum-based chemotherapy and a worse prognosis than the more common serous adenocarcinoma (SAC). To improve survival, the development of new treatment strategies that target CCC more effectively is necessary. Our results show that mTOR is more frequently activated in CCCs than in SACs. Our data have relevance for the design of future clinical studies of first-line treatment for patients with CCC of the ovary. Moreover, the finding of increased expression of phospho-mTOR and greater sensitivity to RAD001 in cisplatin-resistant CCC cells than in cisplatin-sensitive cells suggests a novel treatment option for patients with recurrent disease after cisplatin-based first-line chemotherapy. mTOR (mammalian target of rapamycin) plays a central role in cell proliferation and is regarded as a promising target in cancer therapy including for ovarian cancer. This study aims to examine the role of mTOR as a therapeutic target in clear cell carcinoma (CCC) of the ovary which is regarded as aggressive, chemo-resistant histological subtype. Using tissue microarrays of 98 primary ovarian cancers (52 clear cell carcinomas and 46 serous adenocarcinomas), the expression of phospho-mTOR was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTOR inhibition by RAD001 (everolimus) was examined using 2 pairs of cisplatin-sensitive parental (RMG1 and KOC7C) and cisplatin-resistant human CCC cell lines (RMG1-CR and KOC7C-CR) both in vitro and in vivo. Immunohistochemical analysis demonstrated mTOR was more frequently activated in CCCs than in serous adenocarcinomas (86.6% vs 50%). Treatment with RAD001 markedly inhibited the growth of both RMG1 and KOC7C cells both in vitro and in vivo. Increased expression of phospho-mTOR was observed in cisplatin-resistant RMG1-CR and KOC7C-CR cells, compared to the respective parental cells. This increased expression of phospho-mTOR in cisplatin-resistant cells was associated with increased activation of AKT. RMG1-CR and KOC7C-CR cells showed greater sensitivity to RAD001 than parental RMG1 and KOC7C cells, respectively, in vitro and in vivo. mTOR is frequently activated in CCC and can be a promising therapeutic target in the management of CCC. Moreover, mTOR inhibition by RAD001 may be efficacious as a second-line treatment of recurrent disease in patients previously treated with cisplatin.