mTOR is a promising therapeutic target both in cisplatin-sensitive and cisplatin-resistant clear cell carcinoma of the ovary

Seiji Mabuchi, Chiaki Kawase, Deborah A. Altomare, Kenichirou Morishige, Kenjiro Sawada, Masami Hayashi, Masahiko Tsujimoto, Mareo Yamoto, Andres J. Klein-Szanto, Russell J. Schilder, Masahide Ohmichi, Joseph R. Testa, Tadashi Kimura

Research output: Contribution to journalArticlepeer-review

145 Scopus citations

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 languageEnglish
Pages (from-to)5404-5413
Number of pages10
JournalClinical Cancer Research
Volume15
Issue number17
DOIs
StatePublished - 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

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