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
BMS-777607 induces not only
polyploidy but also senescence. The appearance of senescence was associated with
polyploidy in which β-
galactosidase is exclusively expressed in
polyploid cells.
Survivin expression was increased in
polyploid/senescent cells as analyzed by Western blotting. Increased
survivin accumulated both in the nucleus and cytoplasm and dissociated with condensed
DNA and mitotic spindle at the metaphase. Abnormal accumulation of
survivin also rendered
polyploid/senescent cells insensitive to cytotoxic activities of
YM155,
a DNA damaging agent with a suppressive effect on
survivin gene transcription.
AZD8055, a specific mTOR inhibitor, effectively prevented BMS-777607-induced
polyploidy and senescence and restored
survivin expression and its nuclear localization to normal levels. Although a synergism was not observed,
BMS-777607 plus
AZD8055 increased
cancer cell sensitivity toward different cytotoxic chemotherapeutics. In conclusion, BMS-777607-induced chemoresistance is associated with cell
polyploidy and senescence. Inhibition of mTOR signaling by
AZD8055 prevents BMS-777607-induced
polyploidy/senescence and increases
breast cancer cell chemosensitivity.