1. Antitumor Activity of DFX117 by Dual Inhibition of c-Met and PI3Kα in Non-Small Cell Lung Cancer.
- Author
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Fan, Yanhua, Ding, Huaiwei, Kim, Donghwa, Bach, Duc-Hiep, Hong, Ji-Young, Xu, Yongnan, and Lee, Sang Kook
- Subjects
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ANIMAL experimentation , *APOPTOSIS , *BIOLOGICAL models , *CELL cycle , *CELL lines , *CHALONES , *DRUG delivery systems , *LUNG cancer , *MICE , *MOLECULAR structure , *GENETIC mutation , *PHOSPHOTRANSFERASES , *TREATMENT effectiveness , *IN vitro studies , *IN vivo studies , *CHEMICAL inhibitors - Abstract
Aberrant activation of hepatocyte growth factor (HGF)/c-Met signaling pathway caused by gene amplification or mutation plays an important role in tumorigenesis. Therefore, c-Met is considered as an attractive target for cancer therapy and c-Met inhibitors have been developed with great interests. However, cancers treated with c-Met inhibitors inevitably develop resistance commonly caused by the activation of PI3K/Akt signal transduction pathway. Therefore, the combination of c-Met and PI3Kα inhibitors showed synergistic activities, especially, in c-Met hyperactivated and PIK3CA-mutated cells. In our previous study, we rationally designed and synthesized DFX117(6-(5-(2,4-difluorophenylsulfonamido)-6-methoxypyridin-3-yl)-N-(2-morpholinoethyl) imidazo[1,2-a]pyridine-3-carboxamide) as a novel PI3Kα selective inhibitor. Herein, the antitumor activity and underlying mechanisms of DFX117 against non-small cell lung cancer (NSCLC) cells were evaluated in both in vitro and in vivo animal models. Concurrent targeted c-Met and PI3Kα by DFX117 dose-dependent inhibited the cell growth of H1975 cells (PIK3CA mutation and c-Met amplification) and A549 cells (KRAS mutation). DFX117 subsequently induced G0/G1 cell cycle arrest and apoptosis. These data highlight the significant potential of DFX117 as a feasible and efficacious agent for the treatment of NSCLC patients. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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