Synergistic activities of MET/RON inhibitor BMS-777607 and mTOR inhibitor AZD8055 to polyploid cells derived from pancreatic cancer and cancer stem cells.
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.
Corresponding Author: M.H. Wang, Department of Biomedical Sciences; School of Pharmacy, Texas Tech University Health Sciences Center, 1406 South Coulter Street, Suite 1117, Amarillo, TX 79106. minghai.wang@ttuhsc.edu.
Jun-Ying
JY
Zeng
Sharad
S
Sharma
Yong-Qing
YQ
Zhou
Hang-Ping
HP
Yao
Xing
X
Hu
Ruiwen
R
Zhang
Ming-Hai
MH
Wang
D000631:Aminopyridines / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D009025:Morpholines / Q000008:administration & dosage*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011123:Polyploidy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis; D011728:Pyridones / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects
D000631:Aminopyridines; D009025:Morpholines; C550356:N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; D047428:Protein Kinase Inhibitors; D011728:Pyridones; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met