Potential role of mTORC2 as a therapeutic target in clear cell carcinoma of the ovary.

نویسندگان

  • Takeshi Hisamatsu
  • Seiji Mabuchi
  • Yuri Matsumoto
  • Mahiru Kawano
  • Tomoyuki Sasano
  • Ryoko Takahashi
  • Kenjiro Sawada
  • Kimihiko Ito
  • Hirohisa Kurachi
  • Russell J Schilder
  • Joseph R Testa
  • Tadashi Kimura
چکیده

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.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Companion Diagnostics and Cancer Biomarkers Potential Role of mTORC2 as a Therapeutic Target in Clear Cell Carcinoma of the Ovary

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)], activationofmTORC2wasassessedby immunohistochemistry.Then, thegrowth-inhibitory effecto...

متن کامل

Targeting mTOR Complexes in Ovarian Cancer

The mammalian (mechanistic) target of rapamycin (mTOR) is a serine/threonine kinase that plays a key role in cell growth and proliferation and is regarded as an attractive therapeutic target for cancer therapy. Preclinical investigations have suggested that mTOR complex 1 (mTORC1) and mTORC2 are frequently activated in epithelial ovarian cancer, especially in clear cell carcinoma of the ovary. ...

متن کامل

Bilateral Ovarian Clear Cell Carcinoma Arising in 17 Year Longstanding History of Bilateral Ovarian Endometriosis

Clear cell carcinoma of ovary is uncommon ovarian tumour that arises from surface epithelium of ovary. It has well-known association with ovarian endometriosis. We report here the first case of bilateral clear cell carcinoma of ovaries in a 40-year-old woman with a 17-year history of bilateral ovarian endometriosis. In addition, during the longstanding duration of the endometriosis, the patient...

متن کامل

Apoptosis as a Potential Target in Therapeutic and Vaccine Interventions against Parasitic Diseases

Apoptosis is a physiological cell death that occurs under normal conditions in major biological processes, including the removal of old, damaged, extra, or harmful cells. It plays an important role in natural evolution, tissue homeostasis, removal of cells damaged or infected by viruses, and removal of immune cells activated against self-antigens. The purpose of this review was to examine the r...

متن کامل

Ovarian Small Cell Carcinoma: A Rare Case Report and Review of Literature

Ovarian small cell carcinoma is a rare and highly malignant tumor with poor prognosis. It usually presents in younger females with features of hypercalcemia. The exact histogenesis of the tumor is unclear and it may present as an undifferentiated tumor. In such cases, immunohistochemistry (IHC) plays an important role to confirm the diagnosis. Limited treatment options are available and mainly ...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Molecular cancer therapeutics

دوره 12 7  شماره 

صفحات  -

تاریخ انتشار 2013