Combination of carboplatin and the mTor inhibitor RAD001 is a new therapeutic approach for p53-mutated breast cancer

Abstract #405 Platinum agents are very effective and commonly used chemotherapeutics for the treatment of many solid tumors. However, acquired and intrinsic resistance remains a major obstacle for platinum-based therapy. Recent evidence indicates that mTOR inhibition is a promising strategy to sensitize some p53-wild type solid tumors to conventional chemotherapies. Since p53-mutation is a common phenomenon in breast cancer, we investigated in this study the possibilities of the combined application of carboplatin and the mTOR inhibitor RAD001 in these human breast cancer cells in vitro. Combination of carboplatin and RAD001 resulted in synergistic inhibitions of cell proliferation both in p53-wild type (MCF-7, ZR-75), and in p53-mutated (SKBR-3, BT-474, BT-20), as well as drug resistant (tamoxifen-resistant MCF-7, adriamycin-resistant MCF-7) breast cancer cell lines as analyzed with Calcusyn software. Higher doses of the two drugs resulted in synergistically apoptosis after 24- or 48-hours treatment independent of p53-status of breast cancer cells. Investigation of several cell survival signaling pathways revealed an additively decreased phosphorylation of Erk, STAT3 and Akt after co-treatment suggesting that interference of cell survival signaling may be one of the mechanisms responsible for growth inhibition mediated by this combination. With low doses of the two drugs, we observed impaired cell cycle progression, additively reduced cyclins and CDKs, and enhanced p27 level by flow cytometry analysis and western blot. No rapid apoptosis and caspases-involved cell death were observed. Immunohistological analysis after prolonged treatment with low doses of the two drugs demonstrated that carboplatin alone resulted in the formation of endopolyploid cells in p53-mutated breast cancer cells. RAD001 alone had not such an effect, but strengthened this effect of carboplatin. In addition, decreased level of cyclin B1, the main driver of mitosis, was detected by the co-treatment of the two drugs. These data collectively suggest that the combination use of low doses of carboplatin and RAD001 may present a strategy to overcome the resistance of breast cancer to chemotherapy. It is a promising combination that warrants clinical evaluation. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 405.