Tyrosine kinase inhibitor BMS-777067 is an inhibitor of RON/MET
receptor tyrosine kinases currently under clinical trials. Here, we report the synergistic activity of
BMS-777607 in combination with mTOR inhibitor
AZD8055 in killing chemoresistant
pancreatic cancer and cancer stem cells. Treatment of
pancreatic cancer L3.6pl cells with
BMS-777607 alone inhibited clonogenic growth and moderately induced apoptotic death. However,
BMS-777607 caused extensive
polyploidy in L3.6pl cells through inhibition of
aurora kinase B activity, independent of RON expression. In contrast, L3.6pl-derived cancer stem cells were highly resistant to BMS-777607-induced growth inhibition and apoptosis. The effect of
BMS-777607 on induction of cancer stem cell
polyploidy was also weak. BMS-777607-induced
polyploidy features a predominant cell population with 8N chromosome content in both L3.6pl and cancer stem cells. These cells also showed decreased sensitivity toward chemotherapeutics by increased survival of IC(50) values in response to
doxorubicin,
cisplatin,
methotrexate, 5-fluorouracial, and
gemcitabine. Among a panel of chemical inhibitors that target different signaling
proteins, we found that
BMS-777607 in combination with mTOR inhibitor
AZD8055 exerted synergistic effects on L3.6pl and cancer stem cells. More than 70% of L3.6pl and cancer stem cells lost their viability when both inhibitors were used. Specifically,
BMS-777607 in combination with inhibition of
mTORC2, but not
mTORC1, was responsible for the observed synergism. Our findings demonstrate that
BMS-777607 at therapeutic doses exerts inhibitory activities on
pancreatic cancer cells but also induces
polyploidy insensitive to chemotherapeutics. Combination of
BMS-777607 with
AZD8055 achieves the maximal cytotoxic effect on
pancreatic cancer and cancer stem cells.