The RON
receptor tyrosine kinase is a therapeutic target for
cancer treatment. Here, we report
therapeutic effect and phenotypic change of
breast cancer cells in response to
BMS-777607, a RON
tyrosine kinase inhibitor. Treatment of
breast cancer cells with
BMS-777607 at therapeutic doses inhibited cancerous clonogenic growth but had only minimal effect on cell apoptosis. Significantly,
BMS-777607 induced extensive
polyploidy with multiple sets of chromosomes in
cancer cells. This effect is independent of RON expression. Knockdown of RON in T-47D and ZR-75-1 cells by specific
siRNA did not prevent
polyploid formation. Immunofluorescent analysis of α-
tubulin and γ-
tubulin expression in
polyploid cells revealed that
BMS-777607 disrupts bipolar spindle formation and causes multipolar-like microtubule assembly. Also, both metaphase equatorial alignment and chromosomal segregation were absent in
polyploid cells. These results suggest that cellular mitosis arrests at prophase/pro-metaphase and fails to undergo cytokinesis. By analyzing
kinase-inhibitory profiles,
aurora kinase B was identified as the target molecule inhibited by
BMS-777607. In BMS-777607-treated cells,
aurora kinase B was inhibited followed by protein degradation. Moreover,
BMS-777607 inhibited Ser10 phosphorylation of
histone H3, a substrate of
aurora kinase B. Chemosensitivity analysis indicated the resistance of
polyploid cells toward chemotherapeutics. Treatment with
doxorubicin,
bleomycin,
methotrexate, and
paclitaxel significantly increased cellular IC50 values. These findings highlight the theory that
BMS-777607 acts as a multikinase inhibitor at therapeutic doses and is capable of inducing
polyploidy by inhibiting
aurora kinase B. Increased resistance of
polyploid cells to cytotoxic chemotherapeutics could have a negative impact on targeted
cancer therapy using
BMS-777607.