Abstract P6-15-19: PI3K-MTOR Inhibitor BEZ235 Shows Antitumor Activity Against a Panel of Basal-Like Cells and Potentiates the Antitumor Activity of Taxanes and Vinorelbine

Abstract

Abstract Background: Intracellular signalling pathways associated with the oncogenesis of basal-like breast cancer are relatively unknown. Basal-like breast cancer constitutes 15% of all breast tumors. Although chemotherapy is the only treatment, no data support the use of one agent over others. Furthermore, combinations of chemotherapies with targeted agents against activated signalling pathways have not been explored. Here we have analyzed the action of the dual PI3K-AKT-mTOR pathway inhibitor BEZ235 on a panel of basal-like breast cancer cell lines. Methods: We used several triple negative breast cancer cell lines, and analyzed the action of BEZ235 on their proliferation and cell survival using MTT metabolization and other apoptosis assays. Biochemical experiments were performed to investigate the molecular bases of the action of BEZ235. Experiments in combination with chemotherapies were also performed to identify synergic combinations. Results: PI3K-AKT pathway was activated in most of the cell lines studied. Administration of the dual PI3K-mTOR inhibitor BEZ235 decreased AKT phosphorylation in a dose dependent manner. It also reduced signalling through the mTORC1 and mTORC2 complexes. BEZ235 also decreased proliferation of most cell lines with IC50 values <1 μM. Administration of BEZ 235 with taxanes and vinorelbine showed synergy. Conclusions: The PI3K-AKT-mTOR signalling axis is frequently activated in basal-like cells. The efficient antitumoral effect of the inhibition of this route with BEZ235 indicates that targeting this pathway may be a relevant therapeutic strategy in triple negative breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-19.