mTOR Is a Promising Therapeutic Target Both in Cisplatin-Sensitive and Cisplatin-Resistant Clear Cell Carcinoma of the Ovary

Abstract

Purpose: Mammalian target of rapamycin (mTOR) plays a central role in cell proliferation and is regarded as a promising target in cancer therapy, including for ovarian cancer. This study aimed to examine the role of mTOR as a therapeutic target in clear cell carcinoma of the ovary, which is regarded as an aggressive, chemoresistant histologic subtype. Experimental Design: 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 two pairs of cisplatin-sensitive parental (RMG1 and KOC7C) and cisplatin-resistant human clear cell carcinoma cell lines (RMG1-CR and KOC7C-CR) both in vitro and in vivo. Results: Immunohistochemical analysis showed that mTOR was more frequently activated in clear cell carcinomas than in serous adenocarcinomas (86.6% versus 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 with 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 did parental RMG1 and KOC7C cells, respectively, in vitro and in vivo. Conclusion: mTOR is frequently activated in clear cell carcinoma and can be a promising therapeutic target in the management of clear cell carcinoma. Moreover, mTOR inhibition by RAD001 may be efficacious as a second-line treatment of recurrent disease in patients previously treated with cisplatin. (Clin Cancer Res 2009;15(17):5404–13)