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

ABSTRACT: 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 ? (PDGFR?) 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.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 PDGFR? phosphorylation with that of pazopanib.We classified the SS cell lines as c-MET-dependent or PDGFR?-dependent based upon the differences in the signalling pathway relevant for growth and/or survival. We also found that c-MET and PDGFR? were the primary activators of both phosphatidylinositol 3-kinase/AKT and mitogen-activated protein kinase pathways in c-MET-dependent and PDGFR?-dependent SS cells, respectively. TAS-115 treatment blocked the phosphorylation of PDGFR? 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, PDGFR? phosphorylation, on at least four representative autophosphorylation sites, was impeded by TAS-115 equivalently to pazopanib.These experimental results have demonstrated the significance of c-MET and PDGFR? 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 PDGFR? signalling by functioning as a multiple tyrosine kinase inhibitor to suppress c-MET as well as PDGFR? pathways.

SUBMITTER: Yamada S

PROVIDER: S-EPMC5434537 | biostudies-other | 2017 May

REPOSITORIES: biostudies-other

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

Yamada Shutaro S Imura Yoshinori Y Nakai Takaaki T Nakai Sho S Yasuda Naohiro N Kaneko Keiko K Outani Hidetatsu H Takenaka Satoshi S Hamada Kenichiro K Myoui Akira A Araki Nobuhito N Ueda Takafumi T Itoh Kazuyuki K Yoshikawa Hideki H Naka Norifumi N

BMC cancer 20170516 1

<h4>Background</h4>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 t ...[more]

PMID: 28511645

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Project description:Synovial sarcoma is a highly aggressive but rare form of soft tissue malignancy that primarily affects the extremities of the arms or legs, for which current chemotherapeutic agents have not been proven to be very effective. The cyclin-dependent kinase 4/6-retinoblastoma protein (CDK4/6-Rb) pathway of cell cycle control is known to be aberrant in a large proportion of cancers. Recently, CDK4 inhibitors have successfully been used pre-clinically for the treatment of many human cancers, and in 2015, following the success of clinical trials, the FDA approved the first selective CDK4/6 inhibitor, palbociclib, for the treatment of endocrine therapy resistant breast cancers. However, the expression and therapeutic potential of targeting CDK4 in synovial sarcoma remains unclear. In the present study, we report that CDK4 is highly expressed in human synovial sarcoma, and high CDK4 expressions are associated with poor prognosis in sarcomas patients and the clinical stage and the TNM grade in synovial sarcoma patients. Knockdown of CDK4 with specific small interference RNAs inhibits cell proliferation and enhances apoptotic effects in synovial sarcoma cells. CDK4 inhibitor palbociclib suppresses synovial sarcoma cell proliferation and growth in a dose and time-dependent manner. Palbociclib also inhibits the CDK4/6-Rb signaling pathway and promotes cell apoptosis without changing CDK4/6 protein levels, suggesting that palbociclib only represses the hyper-activation, not the expression of CDK4/6. Flow cytometry analysis reveals that palbociclib induces G1 cell-cycle arrest and apoptotic effects by targeting the CDK4/6-Rb pathway in synovial sarcoma cells. Furthermore, wound healing assays demonstrate that inhibition of the CDK4/6-Rb pathway by palbociclib significantly decreases synovial sarcoma cell migration in vitro. Our study highlights the importance of the CDK4/6-Rb pathway in human synovial sarcoma pathogenesis, and the role of the current selective CDK4/6 inhibitor, palbociclib, as a potential promising targeted therapeutic agent in the treatment of human synovial sarcoma.

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

Publications

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

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