Abstract
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.
| Original language | English |
|---|---|
| Article number | 45332 |
| Journal | Scientific reports |
| Volume | 7 |
| DOIs | |
| Publication status | Published - Mar 28 2017 |
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Activation of ERK1/2 Causes Pazopanib Resistance via Downregulation of DUSP6 in Synovial Sarcoma Cells. / Yokoyama, Nobuhiko; Matsunobu, Tomoya; Matsumoto, Yoshihiro; Fukushi, Jun Ichi; Endo, Makoto; Hatano, Mihoko; Nabeshima, Akira; Fukushima, Suguru; Okada, Seiji; Iwamoto, Yukihide.
In: Scientific reports, Vol. 7, 45332, 28.03.2017.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Activation of ERK1/2 Causes Pazopanib Resistance via Downregulation of DUSP6 in Synovial Sarcoma Cells
AU - Yokoyama, Nobuhiko
AU - Matsunobu, Tomoya
AU - Matsumoto, Yoshihiro
AU - Fukushi, Jun Ichi
AU - Endo, Makoto
AU - Hatano, Mihoko
AU - Nabeshima, Akira
AU - Fukushima, Suguru
AU - Okada, Seiji
AU - Iwamoto, Yukihide
PY - 2017/3/28
Y1 - 2017/3/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85016311573&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85016311573&partnerID=8YFLogxK
U2 - 10.1038/srep45332
DO - 10.1038/srep45332
M3 - Article
C2 - 28350009
AN - SCOPUS:85016311573
VL - 7
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 45332
ER -