title: mTOR is a promising therapeutic target both in cisplatin-sensitive and cisplatin-resistant clear cell carcinoma of the ovary.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. smabuchi@gyne.med.osaka-u.ac.jp
authors.forename: Seiji
authors.initials: S
authors.lastname: Mabuchi
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kawase
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Altomare
authors.forename: Kenichirou
authors.initials: K
authors.lastname: Morishige
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Sawada
authors.forename: Masami
authors.initials: M
authors.lastname: Hayashi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tsujimoto
authors.forename: Mareo
authors.initials: M
authors.lastname: Yamoto
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Klein-Szanto
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Schilder
authors.forename: Masahide
authors.initials: M
authors.lastname: Ohmichi
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Testa
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kimura
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D002945:Cisplatin; D020123:Sirolimus
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