論文 - 詳細
| RRC ID | 52223 |
|---|---|
| 著者 | Yamada S, Imura Y, Nakai T, Nakai S, Yasuda N, Kaneko K, Outani H, Takenaka S, Hamada K, Myoui A, Araki N, Ueda T, Itoh K, Yoshikawa H, Naka N. |
| タイトル | Therapeutic potential of TAS-115 via c-MET and PDGFRα signal inhibition for synovial sarcoma. |
| ジャーナル | BMC Cancer |
| Abstract |
BACKGROUND:The prognosis of synovial sarcoma (SS), an aggressive soft tissue sarcoma, remains poor. We previously reported that c-MET or platelet-derived growth factor receptor α (PDGFRα) signalling pathway is related to SS progression based upon the findings of phospho-receptor tyrosine kinase (RTK) arrays. TAS-115 is a novel c-MET/ vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitor that has been shown to inhibit multiple RTKs. Here we aimed to investigate the therapeutic potential of TAS-115 against SS. METHODS:We first evaluated which signalling pathway was relevant to the viability of three human SS cell lines: Yamato-SS, SYO-1 and HS-SY-II. Next, we assessed the anticancer activity and mechanism of action of TAS-115 in these SS cell lines. Finally, we compared the ability of TAS-115 to inhibit c-MET and PDGFRα phosphorylation with that of pazopanib. RESULTS:We classified the SS cell lines as c-MET-dependent or PDGFRα-dependent based upon the differences in the signalling pathway relevant for growth and/or survival. We also found that c-MET and PDGFRα were the primary activators of both phosphatidylinositol 3-kinase/AKT and mitogen-activated protein kinase pathways in c-MET-dependent and PDGFRα-dependent SS cells, respectively. TAS-115 treatment blocked the phosphorylation of PDGFRα as well as that of c-MET and their downstream effectors, leading to marked growth inhibition in both types of SS cell lines in in vitro and in vivo studies. Furthermore, PDGFRα phosphorylation, on at least four representative autophosphorylation sites, was impeded by TAS-115 equivalently to pazopanib. CONCLUSIONS:These experimental results have demonstrated the significance of c-MET and PDGFRα signalling for growth and/or survival of SS tumours. TAS-115 monotherapy may benefit SS patients whose tumours are dependent upon either c-MET or PDGFRα signalling by functioning as a multiple tyrosine kinase inhibitor to suppress c-MET as well as PDGFRα pathways. |
| 巻・号 | 17(1) |
| ページ | 334 |
| 公開日 | 2017-5-16 |
| DOI | 10.1186/s12885-017-3324-3 |
| PII | 10.1186/s12885-017-3324-3 |
| PMID | 28511645 |
| PMC | PMC5434537 |
| MeSH | Angiogenesis Inhibitors / therapeutic use* Animals Cell Line, Tumor Humans Indazoles Male Mice Mice, Inbred BALB C Mice, Nude Molecular Targeted Therapy / methods Phosphatidylinositol 3-Kinase / metabolism Phosphorylation / drug effects Protein Kinase Inhibitors / therapeutic use* Proto-Oncogene Proteins c-akt / metabolism Proto-Oncogene Proteins c-met / antagonists & inhibitors* Proto-Oncogene Proteins c-met / metabolism Pyrimidines / therapeutic use* Quinolines / therapeutic use* Receptor, Platelet-Derived Growth Factor alpha / antagonists & inhibitors* Receptor, Platelet-Derived Growth Factor alpha / metabolism Sarcoma, Synovial / drug therapy* Sarcoma, Synovial / pathology Signal Transduction / drug effects Sulfonamides / therapeutic use* Thiourea / analogs & derivatives* Thiourea / therapeutic use Xenograft Model Antitumor Assays |
| IF | 3.15 |
| 引用数 | 8 |
| リソース情報 | |
| ヒト・動物細胞 | HS-SY-II(RCB2231) |