Targeting the mTOR pathway in ovarian cancer.

Abstract

e15523 Background: Although improvements in the treatment of ovarian cancer have increased the global prognosis, the metastatic disease is still an incurable situation. Therefore, it is necessary to identify druggable pathways and develop new therapeutic strategies against them. The PI3K-Akt-mTOR pathway regulates several biological functions and it is frequently deregulated in human cancer. In ovarian cancer amplification or mutation of PI3KCA or AKT2 oncogenes, which participate in this route, have been described, and may be the cause of mTOR phosphorylation. Methods: We have investigated the components of the mTOR pathway in ovarian cancer cells, and the action of drugs that target this route. For this purpouse we have used biochemical experiments to identify the activation status of different components of the pathway in several ovarian cancer cell lines. For the evaluation of targeted agents MTT studies complemented with cell cycle analysis, apoptosis assays and biochemical experiments were performed. Results: Expression of the proteins of the components of the two mTOR complexes mTORC1 and mTORC2 was variable in distinct ovarian cancer cell lines. The downstream effector of mTORC2, phospho-Akt Serine 473, was activated under resting conditions in most ovarian cancer cell lines. Interestingly, the mTORC1 downstream effector phospho-S6 was active under resting conditions. Due to the frequent activation of mTOR in these cells, we decided to analyze the effect of the dual PI3K and mTOR inhibitor NVP-BEZ235. This drug inhibited the proliferation of ovarian cancer cells in a dose-dependent manner, and did not interfere with the action of other standard of care treatments. Treatment with the drug inhibited mTOR downstream signalling, as evidenced by dephosphorylation of both Akt and S6. Cell cycle analyses showed that NVP-BEZ235 provoked arrest in the G1 phase, and induced up-regulation of p27. Conclusions: These results suggest that mTOR targeting may represent a convenient strategy for the future treatment of ovarian cancer. No significant financial relationships to disclose.