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.
Original language | English |
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Pages (from-to) | 5404-5413 |
Number of pages | 10 |
Journal | Clinical Cancer Research |
Volume | 15 |
Issue number | 17 |
DOIs | |
State | Published - Sep 1 2009 |
Keywords
- Adenocarcinoma, Clear Cell/drug therapy
- Animals
- Antineoplastic Agents/therapeutic use
- Cell Line, Tumor
- Cisplatin/therapeutic use
- Drug Resistance, Neoplasm/drug effects
- Everolimus
- Female
- Humans
- Immunosuppressive Agents/pharmacology
- Mice
- Mice, Nude
- Ovarian Neoplasms/drug therapy
- Protein Kinases/drug effects
- Proto-Oncogene Proteins c-akt/metabolism
- Sirolimus/analogs & derivatives
- TOR Serine-Threonine Kinases
- Tissue Array Analysis
- Xenograft Model Antitumor Assays