[Background] NVP-BEZ235 (BEZ235) is a novel, orally bioavailable imidazoquinoline that potently and reversibly inhibits class 1 PI3K activity by binding to its ATP-binding domain. BEZ235 also binds directly to the mTOR ATP-binding domain and directly inhibits its catalytic activity, thereby inhibiting both TORC1 and TORC2. BEZ235 is currently in phase I testing in patients with solid tumors. There are few reports on the activity of BEZ235 against ovarian carcinoma cells. Ovarian clear cell carcinoma (CCC) has shown the resistance to the standard chemotherapy for epithelial ovarian cancer (EOC). Therefore, patients with CCC have a worse prognosis than those with ovarian serous adenocarcinoma (SAC), which is a dominant subtype in EOC. However, little has been known about genetic alterations in each histologic subtype of EOC. Recently, it has shown that CCC has a high frequency of activating PIK3CA mutations. The purpose of the current study was to determine whether the drug targeting the PI3K-Akt-mTOR pathway suppresses cell proliferation of CCC.

[Material& Methods] We used eight CCC cell lines (KK, OVISE, SMOV-2, KOC-7c, TUOC-1, OVTOKO, OVMANA, and RMG-I) and four SAC cell lines (SHIN-3, TUOS-4, KOC-2s, SK-OV-3) in this study. IC50 to BEZ235 was determined on the basis of the dose-effect curves, using WST-8 assay. Protein expressions of Akt, phospho(p)-Akt(Ser473), mTOR, pmTOR(Ser2448), p70S6K, pp70S6K(Thr389), 4E-BP1, and p4E-BP1(Ser37/46) were examined by western blotting.

[Results] IC50 to BEZ235 for CCC cell lines ranged from 44 to 777 nM and those for SAC cell lines ranged from 989 to 25400 nM. All 8 CCC cell lines showed Akt, mTOR, pmTOR, and p70S6K expressions. Six cell lines showed pAkt expression, and 2 of the 6 cell lines showed both pAkt and p4E-BP1 expressions. Remaining 2 cell lines showed pp70S6K expression. pAkt, p-p70S6K and p4E-BP1 expression in CCC cells were suppressed after exposure to BEZ235 in a dose-dependent manner.

[Conclusion] These results suggest that the PI3K/Akt/mTOR pathway is a potential therapeutic target for CCC and that NVP-BEZ235 is worth exploring as therapeutic agents for CCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4497. doi:10.1158/1538-7445.AM2011-4497