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

2018; Wiley; Volume: 110; Issue: 1 Linguagem: Inglês

10.1111/cas.13840

1349-7006

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,

Microtubule and mitosis dynamics

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 EZH 2 , which encode the catalytic subunits of Polycomb repressive complex 2 ( PRC 2), than non‐ SP cells, suggesting that EZH 1 as well as EZH 2 contributes to the stemness maintenance of the MM cells and that targeting both EZH 1/2 is potentially a significant therapeutic approach for eradicating myeloma stem cells. A novel orally bioavailable EZH 1/2 dual inhibitor, OR ‐S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH 2 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, PRC 2 directly regulated WNT signaling in MM , and overactivation of this signaling induced by dual inhibition of EZH 1/2 eradicated myeloma stem cells and negatively affected tumorigenesis, suggesting that repression of WNT signaling by PRC 2 plays an important role in stemness maintenance of MM cells. Our results show the role of EZH 1/2 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 .