Prevention of BMS-777607-induced polyploidy/senescence by mTOR inhibitor AZD8055 sensitizes breast cancer cells to cytotoxic chemotherapeutics.

ABSTRACT: Targeted inhibition of MET/RON signaling by tyrosine kinase inhibitor BMS-777607 for cancer treatment is currently under clinical trials. We have previously shown that BMS-777607 induces chemoresistance in vitro by causing polyploidy, which hampers therapeutic efficacy. Here, we studied polyploidy-associated senescence induced by BMS-777607 in breast cancer cells and its prevention by mTOR inhibitor AZD8055, leading to increased chemosensitivity. In breast cancer T-47D and ZR-75-1 cells, BMS-777607 induced phenotypic changes including enlarged cellular size, flattened morphology, increased DNA content, and activity of senescence-associated β-galactosidase. These changes were accompanied by increased p21/WAF1 expression and decreased Retinoblastoma Ser(780) phosphorylation, indicating that

SUBMITTER: Sharma S 

PROVIDER: S-EPMC5528636 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature