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

Nobuhiko Yokoyama, Tomoya Matsunobu, Yoshihiro Matsumoto, Jun Ichi Fukushi, Makoto Endo, Mihoko Hatano, Akira Nabeshima, Suguru Fukushima, Seiji Okada, Yukihide Iwamoto

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 languageEnglish
Article number45332
JournalScientific reports
Volume7
DOIs
Publication statusPublished - Mar 28 2017

Fingerprint

Dual Specificity Phosphatase 6
Synovial Sarcoma
Down-Regulation
Clone Cells
Mitogen-Activated Protein Kinase Kinases
pazopanib

All Science Journal Classification (ASJC) codes

  • General

Cite this

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 journalArticle

Yokoyama, Nobuhiko ; Matsunobu, Tomoya ; Matsumoto, Yoshihiro ; Fukushi, Jun Ichi ; Endo, Makoto ; Hatano, Mihoko ; Nabeshima, Akira ; Fukushima, Suguru ; Okada, Seiji ; Iwamoto, Yukihide. / Activation of ERK1/2 Causes Pazopanib Resistance via Downregulation of DUSP6 in Synovial Sarcoma Cells. In: Scientific reports. 2017 ; Vol. 7.
@article{bbadfbd639a34226bc86b16c0f91f5ba,
title = "Activation of ERK1/2 Causes Pazopanib Resistance via Downregulation of DUSP6 in Synovial Sarcoma Cells",
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.",
author = "Nobuhiko Yokoyama and Tomoya Matsunobu and Yoshihiro Matsumoto and Fukushi, {Jun Ichi} and Makoto Endo and Mihoko Hatano and Akira Nabeshima and Suguru Fukushima and Seiji Okada and Yukihide Iwamoto",
year = "2017",
month = "3",
day = "28",
doi = "10.1038/srep45332",
language = "English",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

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 -