Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma

Makoto Nakagawa, Shuhei Fujita, Takuo Katsumoto, Kazutsune Yamagata, Yoko Ogawara, Ayuna Hattori, Yuki Kagiyama, Daisuke Honma, Kazushi Araki, Tatsuya Inoue, Ayako Kato, Koichiro Inaki, Chisa Wada, Yoshimasa Ono, Masahide Yamamoto, Osamu Miura, Yasuharu Nakashima, Issay Kitabayashi

研究成果: ジャーナルへの寄稿記事

抄録

Multiple myeloma (MM) is an incurable hematological malignancy caused by accumulation of abnormal clonal plasma cells. Despite the recent development of novel therapies, relapse of MM eventually occurs as a result of a remaining population of drug-resistant myeloma stem cells. Side population (SP) cells show cancer stem cell-like characteristics in MM; thus, targeting these cells is a promising strategy to completely cure this malignancy. Herein, we showed that SP cells expressed higher levels of enhancer of zeste homolog (EZH) 1 and EZH2, which encode the catalytic subunits of Polycomb repressive complex 2 (PRC2), than non-SP cells, suggesting that EZH1 as well as EZH2 contributes to the stemness maintenance of the MM cells and that targeting both EZH1/2 is potentially a significant therapeutic approach for eradicating myeloma stem cells. A novel orally bioavailable EZH1/2 dual inhibitor, OR-S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH2 inhibitor in vitro and in vivo, including a unique patient-derived xenograft model. Moreover, long-term continuous dosing of OR-S1 completely cured mice bearing orthotopic xenografts. Additionally, PRC2 directly regulated WNT signaling in MM, and overactivation of this signaling induced by dual inhibition of EZH1/2 eradicated myeloma stem cells and negatively affected tumorigenesis, suggesting that repression of WNT signaling by PRC2 plays an important role in stemness maintenance of MM cells. Our results show the role of EZH1/2 in the maintenance of myeloma stem cells and provide a preclinical rationale for therapeutic application of OR-S1, leading to significant advances in the treatment of MM.

元の言語英語
ページ(範囲)194-208
ページ数15
ジャーナルCancer Science
110
発行部数1
DOI
出版物ステータス出版済み - 1 1 2019

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Neoplastic Stem Cells
Multiple Myeloma
Polycomb Repressive Complex 2
Side-Population Cells
Stem Cells
Maintenance
Heterografts
Hematologic Neoplasms
Therapeutics
Plasma Cells
Enhancer of Zeste Homolog 2 Protein
Population
Catalytic Domain
Carcinogenesis
Recurrence
Pharmaceutical Preparations
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

これを引用

Nakagawa, M., Fujita, S., Katsumoto, T., Yamagata, K., Ogawara, Y., Hattori, A., ... Kitabayashi, I. (2019). Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma. Cancer Science, 110(1), 194-208. https://doi.org/10.1111/cas.13840

Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma. / Nakagawa, Makoto; Fujita, Shuhei; Katsumoto, Takuo; Yamagata, Kazutsune; Ogawara, Yoko; Hattori, Ayuna; Kagiyama, Yuki; Honma, Daisuke; Araki, Kazushi; Inoue, Tatsuya; Kato, Ayako; Inaki, Koichiro; Wada, Chisa; Ono, Yoshimasa; Yamamoto, Masahide; Miura, Osamu; Nakashima, Yasuharu; Kitabayashi, Issay.

:: Cancer Science, 巻 110, 番号 1, 01.01.2019, p. 194-208.

研究成果: ジャーナルへの寄稿記事

Nakagawa, M, Fujita, S, Katsumoto, T, Yamagata, K, Ogawara, Y, Hattori, A, Kagiyama, Y, Honma, D, Araki, K, Inoue, T, Kato, A, Inaki, K, Wada, C, Ono, Y, Yamamoto, M, Miura, O, Nakashima, Y & Kitabayashi, I 2019, 'Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma', Cancer Science, 巻. 110, 番号 1, pp. 194-208. https://doi.org/10.1111/cas.13840
Nakagawa, Makoto ; Fujita, Shuhei ; Katsumoto, Takuo ; Yamagata, Kazutsune ; Ogawara, Yoko ; Hattori, Ayuna ; Kagiyama, Yuki ; Honma, Daisuke ; Araki, Kazushi ; Inoue, Tatsuya ; Kato, Ayako ; Inaki, Koichiro ; Wada, Chisa ; Ono, Yoshimasa ; Yamamoto, Masahide ; Miura, Osamu ; Nakashima, Yasuharu ; Kitabayashi, Issay. / Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma. :: Cancer Science. 2019 ; 巻 110, 番号 1. pp. 194-208.
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abstract = "Multiple myeloma (MM) is an incurable hematological malignancy caused by accumulation of abnormal clonal plasma cells. Despite the recent development of novel therapies, relapse of MM eventually occurs as a result of a remaining population of drug-resistant myeloma stem cells. Side population (SP) cells show cancer stem cell-like characteristics in MM; thus, targeting these cells is a promising strategy to completely cure this malignancy. Herein, we showed that SP cells expressed higher levels of enhancer of zeste homolog (EZH) 1 and EZH2, which encode the catalytic subunits of Polycomb repressive complex 2 (PRC2), than non-SP cells, suggesting that EZH1 as well as EZH2 contributes to the stemness maintenance of the MM cells and that targeting both EZH1/2 is potentially a significant therapeutic approach for eradicating myeloma stem cells. A novel orally bioavailable EZH1/2 dual inhibitor, OR-S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH2 inhibitor in vitro and in vivo, including a unique patient-derived xenograft model. Moreover, long-term continuous dosing of OR-S1 completely cured mice bearing orthotopic xenografts. Additionally, PRC2 directly regulated WNT signaling in MM, and overactivation of this signaling induced by dual inhibition of EZH1/2 eradicated myeloma stem cells and negatively affected tumorigenesis, suggesting that repression of WNT signaling by PRC2 plays an important role in stemness maintenance of MM cells. Our results show the role of EZH1/2 in the maintenance of myeloma stem cells and provide a preclinical rationale for therapeutic application of OR-S1, leading to significant advances in the treatment of MM.",
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AU - Nakagawa, Makoto

AU - Fujita, Shuhei

AU - Katsumoto, Takuo

AU - Yamagata, Kazutsune

AU - Ogawara, Yoko

AU - Hattori, Ayuna

AU - Kagiyama, Yuki

AU - Honma, Daisuke

AU - Araki, Kazushi

AU - Inoue, Tatsuya

AU - Kato, Ayako

AU - Inaki, Koichiro

AU - Wada, Chisa

AU - Ono, Yoshimasa

AU - Yamamoto, Masahide

AU - Miura, Osamu

AU - Nakashima, Yasuharu

AU - Kitabayashi, Issay

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N2 - Multiple myeloma (MM) is an incurable hematological malignancy caused by accumulation of abnormal clonal plasma cells. Despite the recent development of novel therapies, relapse of MM eventually occurs as a result of a remaining population of drug-resistant myeloma stem cells. Side population (SP) cells show cancer stem cell-like characteristics in MM; thus, targeting these cells is a promising strategy to completely cure this malignancy. Herein, we showed that SP cells expressed higher levels of enhancer of zeste homolog (EZH) 1 and EZH2, which encode the catalytic subunits of Polycomb repressive complex 2 (PRC2), than non-SP cells, suggesting that EZH1 as well as EZH2 contributes to the stemness maintenance of the MM cells and that targeting both EZH1/2 is potentially a significant therapeutic approach for eradicating myeloma stem cells. A novel orally bioavailable EZH1/2 dual inhibitor, OR-S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH2 inhibitor in vitro and in vivo, including a unique patient-derived xenograft model. Moreover, long-term continuous dosing of OR-S1 completely cured mice bearing orthotopic xenografts. Additionally, PRC2 directly regulated WNT signaling in MM, and overactivation of this signaling induced by dual inhibition of EZH1/2 eradicated myeloma stem cells and negatively affected tumorigenesis, suggesting that repression of WNT signaling by PRC2 plays an important role in stemness maintenance of MM cells. Our results show the role of EZH1/2 in the maintenance of myeloma stem cells and provide a preclinical rationale for therapeutic application of OR-S1, leading to significant advances in the treatment of MM.

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