title: Potential role of mTORC2 as a therapeutic target in clear cell carcinoma of the ovary.
abstract: The goal of this study was to examine the role of mTOR complex 2 (mTORC2) as a therapeutic target in ovarian clear cell carcinoma (CCC), which is regarded as an aggressive, chemoresistant histologic subtype. Using tissue microarrays of 98 primary ovarian cancers [52 CCCs and 46 serous adenocarcinomas (SAC)], activation of mTORC2 was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTORC2-targeting therapy, as well as the role of mTORC2 signaling as a mechanism for acquired resistance to the mTOR complex 1 (mTORC1) inhibitor RAD001 in ovarian CCC, were examined using two pairs of RAD001-sensitive parental (RMG2 and HAC2) and RAD001-resistant CCC cell lines (RMG2-RR and HAC2-RR). mTORC2 was more frequently activated in CCCs than in SACs (71.2% vs. 45.7%). Simultaneous inhibition of mTORC1 and mTORC2 by AZD8055 markedly inhibited the proliferation of both RAD001-sensitive and -resistant cells in vitro. Treatment with RAD001 induced mTORC2-mediated AKT activation in RAD001-sensitive CCC cells. Moreover, increased activation of mTORC2-AKT signaling was observed in RAD001-resistant CCC cells compared with the respective parental cells. Inhibition of mTORC2 during RAD001 treatment enhanced the antitumor effect of RAD001 and prevented CCC cells from acquiring resistance to RAD001. In conclusion, mTORC2 is frequently activated, and can be a promising therapeutic target, in ovarian CCCs. Moreover, mTORC2-targeted therapy may be efficacious in a first-line setting as well as for second-line treatment of recurrent disease developing after RAD001-treatment.
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hisamatsu
authors.forename: Seiji
authors.initials: S
authors.lastname: Mabuchi
authors.forename: Yuri
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Mahiru
authors.initials: M
authors.lastname: Kawano
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Sasano
authors.forename: Ryoko
authors.initials: R
authors.lastname: Takahashi
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Sawada
authors.forename: Kimihiko
authors.initials: K
authors.lastname: Ito
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kurachi
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Schilder
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* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068338:Everolimus; D005260:Female; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D000068338:Everolimus; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus