MTOR inhibition is a rational target for the treatment of endometrial cancer

Abstract

5076 Background: The finding of PTEN mutations in 40–60% of endometrial cancers suggests this pathway is important in the pathogenesis of this disease. Loss of PTEN leads to constitutive activation of AKT, which in turn leads to up-regulation of the mammalian target of rapamycin (mTOR). mTOR inhibition leads to decreased activation of the p70s6 kinase (S6K), a downstream protein directly and indirectly associated with cell proliferation. Currently, several mTOR inhibitors are under clinical investigation for the treatment of cancer. The purpose of this study is to evaluate the expression of mTOR and S6K in a series of endometrial cancers. Methods: Immunohistochemistry was performed using sections of tumors from 95 patients: 39 with endometrioid endometrial carcinoma (EEC), 37 with uterine serous carcinoma (USC), and 19 with recurrent endometrial cancer (REC). Sections were stained with commercially available antibodies for phosphorylated (phospho-) mTOR and phospho-S6K. Positive expression was defined as moderate (2+) to strong (3+) staining in >20% of the tumor cells. In addition, western blot analysis was performed on 5 endometrial cancer cell lines (HEC-1-A, HEC-1-B, Ishikawa, KLE, RL95–2) to determine the presence of mTOR and phospho-mTOR. Results: Phospho-mTOR expression was observed in 53% (50/95) of the tumors. Phospho-S6K expression was observed in 69% (66/95) of the tumors. 46% (18/39) of the EEC, 62% (23/37) of the USC, and 47% (9/19) of the REC expressed phospho-mTOR. 62% (24/39) of the EEC, 68% (25/37), and 89% (17/19) of REC expressed phospho-S6K. There was an association between mTOR and S6K expression (p=0.06). In addition, all of the cell lines expressed mTOR and 4 of 5 (80%) expressed phospho-mTOR (HEC-1-A, HEC-1-B, KLE, RL95–2). Conclusions: Phospho-mTOR and phospho-S6K are expressed in most endometrial cancers. There is an association between expression of mTOR and S6K. In addition, mTOR and phospho-mTOR are present in endometrial cancer cell lines. These results suggest that mTOR inhibitors may be useful for the treatment of endometrial cancer. We are initiating a phase II trial evaluating an mTOR inhibitor for the treatment of recurrent endometrial cancer. No significant financial relationships to disclose.