Antitumor Activity of DFX117 by Dual Inhibition of c-Met and PI3Kα in Non-Small Cell Lung Cancer
Autor: | Ji-Young Hong, Yongnan Xu, Duc-Hiep Bach, Donghwa Kim, Sang Kook Lee, Yanhua Fan, Huai-Wei Ding |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Cancer Research Cell cycle checkpoint C-Met non-small cell lung cancer (NSCLC) medicine.disease_cause lcsh:RC254-282 Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine PI3K/AKT/mTOR pathway A549 cell dual inhibitor of PI3K and Met Chemistry Cell growth apoptosis lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease 030104 developmental biology Oncology cell cycle arrest 030220 oncology & carcinogenesis 3-substituted imidazo[1 2-a]pyridine (DFX117) Cancer research Hepatocyte growth factor Carcinogenesis medicine.drug |
Zdroj: | Cancers Volume 11 Issue 5 Cancers, Vol 11, Iss 5, p 627 (2019) |
ISSN: | 2072-6694 |
DOI: | 10.3390/cancers11050627 |
Popis: | 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 PI3K&alpha 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 PI3K&alpha 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 PI3K&alpha 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. |
Databáze: | OpenAIRE |
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