A novel multi‐kinase inhibitor pazopanib suppresses growth of synovial sarcoma cells through inhibition of the PI3K‐AKT pathway

Hosaka, Seiichi; Horiuchi, Keisuke; Yoda, Masaki; Nakayama, Robert; Tohmonda, Takahide; Susa, Michiro; Nakamura, Masaya; Chiba, Kazuhiro; Toyama, Yoshiaki; Morioka, Hideo

doi:10.1002/jor.22091

Cited by 32 publications

(27 citation statements)

References 24 publications

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“…However, there have only been a few reports that have demonstrated the molecular mechanism by which pazopanib inhibits the growth of a variety of tumors [15,36-40]. Kumar used a cell-free assay system to show kinase activity of pazopanib and found that pazopanib had an IC 50 value of 6 μmol/L for inhibiting c-MET activity [15].…”

Section: Discussionmentioning

confidence: 99%

Establishment of a novel clear cell sarcoma cell line (Hewga-CCS), and investigation of the antitumor effects of pazopanib on Hewga-CCS

et al. 2014

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BackgroundClear cell sarcoma (CCS) is a therapeutically unresolved, aggressive, soft tissue sarcoma (STS) that predominantly affects young adults. This sarcoma is defined by t(12;22)(q13;q12) translocation, which leads to the fusion of Ewing sarcoma gene (EWS) to activating transcription factor 1 (ATF1) gene, producing a chimeric EWS-ATF1 fusion gene. We established a novel CCS cell line called Hewga-CCS and developed an orthotopic tumor xenograft model to enable comprehensive bench-side investigation for intensive basic and preclinical research in CCS with a paucity of experimental cell lines.MethodsHewga-CCS was derived from skin metastatic lesions of a CCS developed in a 34-year-old female. The karyotype and chimeric transcript were analyzed. Xenografts were established and characterized by morphology and immunohistochemical reactivity. Subsequently, the antitumor effects of pazopanib, a recently approved, novel, multitargeted, tyrosine kinase inhibitor (TKI) used for the treatment of advanced soft tissue sarcoma, on Hewga-CCS were assessed in vitro and in vivo.ResultsHewga-CCS harbored the type 2 EWS-ATF1 transcript. Xenografts morphologically mimicked the primary tumor and expressed S-100 protein and antigens associated with melanin synthesis (Melan-A, HMB45). Pazopanib suppressed the growth of Hewga-CCS both in vivo and in vitro. A phospho-receptor tyrosine kinase array revealed phosphorylation of c-MET, but not of VEGFR, in Hewga-CCS. Subsequent experiments showed that pazopanib exerted antitumor effects through the inhibition of HGF/c-MET signaling.ConclusionsCCS is a rare, devastating disease, and our established CCS cell line and xenograft model may be a useful tool for further in-depth investigation and understanding of the drug-sensitivity mechanism.

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Section: Discussionmentioning

confidence: 99%

Establishment of a novel clear cell sarcoma cell line (Hewga-CCS), and investigation of the antitumor effects of pazopanib on Hewga-CCS

et al. 2014

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“…5,23,24 Previous studies have indicated another potential factor in the Akt/mTOR pathway: the activation of receptor tyrosine kinases or cytokine receptors. Epidermal growth factor receptor (EGFR), 14,25,26 insulin-like growth factor-1 receptor (IGF1R), 14,27 and plateletderived growth factor receptor a (PDGFRa) 6,28,29 have been proven responsible for Akt/mTOR pathway activation in SS, and some preclinical studies have lent credence to targeting this pathway. 6,29 Clinical trials of molecular targeting drugs also have been undertaken in STS.…”

Section: Discussionmentioning

confidence: 99%

“…Epidermal growth factor receptor (EGFR), 14,25,26 insulin-like growth factor-1 receptor (IGF1R), 14,27 and plateletderived growth factor receptor a (PDGFRa) 6,28,29 have been proven responsible for Akt/mTOR pathway activation in SS, and some preclinical studies have lent credence to targeting this pathway. 6,29 Clinical trials of molecular targeting drugs also have been undertaken in STS. Ridaforolimus, an mTOR inhibitor, produced significantly prolonged progression-free survival in a clinical trial targeting advanced STS, 7 although no significant difference was indicated for OS.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Therefore, the Akt/mTOR pathway is regarded as oncogenic and has the potential to be a therapeutic target. Several previous studies have demonstrated activation of the Akt/mTOR pathway and its contribution to cell survival and proliferation in SS cell lines [3][4][5][6] as well as the effects of the clinical application of therapeutic agents targeting mTOR in soft tissue sarcoma (STS). 7 The prognostic impact of the activation of this pathway, however, remains to be clarified.…”

Section: Introductionmentioning

confidence: 99%

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Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

Setsu

Kohashi

Fushimi

et al. 2013

Cancer

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BACKGROUND:The Akt/mammalian target of rapamycin (mTOR) pathway, downstream from phosphatidylinositol 3-kinase (PI3K), mediates cell survival and proliferation. Although this pathway reportedly contributes to the progression of synovial sarcoma, its prognostic impact has not been clarified. METHODS: The authors analyzed clinicopathologic data and phosphorylation status of Akt (a serine/threonine kinase also known as protein kinase B), mTOR, the eukaryotic translation initiation factor 4E binding protein (4E-BP1), and the S6 ribosomal protein by immunohistochemical analysis of 120 formalin-fixed, paraffin-embedded samples and by Western blot analysis of 24 frozen samples from 112 patients with synovial sarcoma. RESULTS: Akt, mTOR, 4E-BP1, and S6 were activated in 76.5%, 67.6%, 59.6%, and 42.6% of samples, respectively. Immunohistochemically positive phosphorylated (p) mTOR (pmTOR) and p4E-BP1 results were correlated with higher mitotic activity, and positive p4E-BP1 results were correlated with greater necrosis. No mutations around the hot spots in the PI3K catalytic subunit a (PI3KCA) and Akt1 genes were observed. In multivariate analysis of clinicopathologic parameters, frequent mitosis was a risk factor for shorter overall survival; and male sex, visceral location, larger tumor size, and frequent mitosis were identified as risk factors for shorter event-free survival. Positive pmTOR and p4E-BP1 results were correlated significantly with shorter overall survival, and positive p4E-BP1 results were correlated with shorter event-free survival in univariate analysis. Positive pAkt results were associated significantly with shorter event-free survival in multivariate analysis. CONCLUSIONS: In this study, the Akt/mTOR pathway was activated and was associated with worse clinical and pathologic behavior in patients with synovial sarcoma. The authors propose that this pathway may have potential as a therapeutic target.

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“…1a. It has been reported that pazopanib mainly targets PDGFRα and induces G1/S arrest by inhibition of the PDGFRα–PI3K–Akt pathway in SS cells10. We therefore performed cell cycle analysis using flow cytometry in order to determine the cell cycle status of pazopanib-resistant and parental cells in the presence or absence of pazopanib.…”

Section: Resultsmentioning

confidence: 99%

Activation of ERK1/2 Causes Pazopanib Resistance via Downregulation of DUSP6 in Synovial Sarcoma Cells

Yokoyama

Matsunobu

Matsumoto

et al. 2017

Sci Rep

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Synovial sarcoma (SS) is a rare high-grade malignant mesenchymal tumour with a relatively poor prognosis despite intensive multimodal therapy. Although pazopanib, a multi-kinase inhibitor, is often used for advanced SS, most cases eventually become resistant to pazopanib. In the present study, we investigated the mechanisms of acquired pazopanib resistance in SS. To examine acquired pazopanib resistance, two SS cell lines, SYO-1 and HS-SY-II, were isolated after multiple selection steps with increasing concentrations of pazopanib. SYO-1 was also used in vivo. Then, pazopanib-resistant clones were investigated to assess potential mechanisms of acquired pazopanib resistance. Stable pazopanib-resistant clones were established and exhibited enhanced cell cycle progression, cell growth with increased ERK1/2 phosphorylation, and higher sensitivity than parental cells to a MEK-inhibitor, trametinib, both in vitro and in vivo. Furthermore, addition of low-dose trametinib partially reversed the pazopanib resistance. In the pazopanib-resistant clones, dual specificity phosphatase 6 (DUSP6) was downregulated. Inhibition of DUSP6 expression in parental HS-SY-II cells partially recapitulated acquired pazopanib resistance. Acquired pazopanib resistance in SS was associated with activation of ERK1/2 through downregulation of DUSP6 expression. Simultaneous treatment with pazopanib and a MEK inhibitor could be a promising strategy to overcome pazopanib resistance in SS.

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A novel multi‐kinase inhibitor pazopanib suppresses growth of synovial sarcoma cells through inhibition of the PI3K‐AKT pathway

Cited by 32 publications

References 24 publications

Establishment of a novel clear cell sarcoma cell line (Hewga-CCS), and investigation of the antitumor effects of pazopanib on Hewga-CCS

Establishment of a novel clear cell sarcoma cell line (Hewga-CCS), and investigation of the antitumor effects of pazopanib on Hewga-CCS

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

Activation of ERK1/2 Causes Pazopanib Resistance via Downregulation of DUSP6 in Synovial Sarcoma Cells

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