Therapeutic potential of TAS-115 via c-MET and PDGFR\u03b1 signal inhibition for synovial sarcoma

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

doi:10.1186/s12885-017-3324-3

Nobuhito Araki, Satoshi Takenaka

Open Access

https://doi.org/10.1186/s12885-017-3324-3

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Abstract

BackgroundThe 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.MethodsWe 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.ResultsWe 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.ConclusionsThese 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.

Highlights

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 was relevant for SS progression, based upon the findings of phospho-receptor tyrosine kinase (RTK) arrays [8]. cMET, an RTK encoded by the c-met proto-oncogene, is known to be a hepatocyte growth factor (HGF) receptor [9]
Immunoblot analyses revealed that c-MET was activated in Yamato-SS cells, whereas PDGFRα was activated in all three SS cell lines (Fig. 1a)

Summary

Introduction

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. We previously reported that c-MET or platelet-derived growth factor receptor α (PDGFRα) signalling pathway was relevant for SS progression, based upon the findings of phospho-receptor tyrosine kinase (RTK) arrays [8]. Hosaka et al showed that pazopanib suppressed the growth of SYO-1 and HS-SY-II cells through inhibition of the PDGFRα and phosphatidylinositol 3-kinase (PI3K)/AKT pathways [14]. Based upon these studies, we hypothesize that inhibition of the c-MET or PDGFRα signalling pathway would be a therapeutic strategy for the treatment of SS

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