Journal Article

Therapeutic potential of TAS-115 via c-MET and PDGFRα signal inhibition for synovial sarcoma

Outani, Hidetatsu, Nakai, Takaaki, Ueda, Takafumi, Itoh, Kazuyuki, Kaneko, Keiko, Takenaka, Satoshi, Yoshikawa, Hideki, Hamada, Kenichiro, Imura, Yoshinori, Yasuda, Naohiro, Nakai, Sho, Myoui, Akira, Araki, Nobuhito, Yamada, Shutaro, Naka, Norifumi

2017

Overview

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.

• Publisher: BioMed Central,BMC
• Subject: Angiogenesis Inhibitors - therapeutic use / Animals / Biomedical and Life Sciences / Biomedicine / C-MET / Cancer Research / Cell Line, Tumor / Experimental therapeutics and drug development / Health Promotion and Disease Prevention / Humans / Male / Medicine/Public Health / Mice / Mice, Inbred BALB C / Mice, Nude / Molecular targeted therapy / Molecular Targeted Therapy - methods / Oncology / PDGFRα / 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 / Research Article / Sarcoma, Synovial - drug therapy / Sarcoma, Synovial - pathology / Signal Transduction - drug effects / Sulfonamides - therapeutic use / Surgical Oncology / Synovial sarcoma / TAS-115 / Thiourea - analogs & derivatives / Thiourea - therapeutic use / Xenograft Model Antitumor Assays