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Mechanisms of Action and Resistance in Histone Methylation-targeted Therapy by Makoto Yamagishi; Yuta Kuze; Seiichiro Kobayashi; Makoto Nakashima; Satoko Morishima; Toyotaka Kawamata; Junya Makiyama; Kako Suzuki; Masahide Seki; Kazumi Abe; Kiyomi Imamura; Eri Watanabe; Kazumi Tsuchiya; Isao Yasumatsu; Gensuke Takayama; Yoshiyuki Hizukuri; Kazumi Ito; Yukihiro Taira; Yasuhito Nannya; Arinobu Tojo; Toshiki Watanabe; Shinji Tsutsumi; Yutaka Suzuki; Kaoru Uchimaru is a Physics and Astronomy article available to read on EtoBox.
What is Mechanisms of Action and Resistance in Histone Methylation-targeted Therapy about?
Epigenomes enable the rectification of disordered cancer gene expression, thereby providing new targets for pharmacological interventions. The clinical utility of targeting histone H3 lysine trimethylation (H3K27me3) as an epigenetic hallmark has been demonstrated^1–7^. However, in actual therapeutic settings, the mechanism by which H3K27me3-targeting therapies exert their effects and the response of tumour cells remain unclear. Here we show the potency and mechanisms of action and resistance of the EZH1–EZH2 dual inhibitor valemetostat in clinical trials of patients with adult T cell leukaemia/lymphoma. Administration of valemetostat reduced tumour size and demonstrated durable clinical response in aggressive lymphomas with multiple genetic mutations. Integrative single-cell analyses showed that valemetostat abolishes the highly condensed chromatin structure formed by the plastic H3K27me3 and neutralizes multiple gene loci, including tumour suppressor genes. Nevertheless, subsequent long-term treatment encounters the emergence of resistant clones with reconstructed aggregate chromatin that closely resemble the pre-dose state. Acquired mutations at the PRC2–compound interface resul
Who reads Mechanisms of Action and Resistance in Histone Methylation-targeted Therapy?
It is typically read by researchers, students, and practitioners in Physics and Astronomy.
- Author
- Makoto Yamagishi; Yuta Kuze; Seiichiro Kobayashi; Makoto Nakashima; Satoko Morishima; Toyotaka Kawamata; Junya Makiyama; Kako Suzuki; Masahide Seki; Kazumi Abe; Kiyomi Imamura; Eri Watanabe; Kazumi Tsuchiya; Isao Yasumatsu; Gensuke Takayama; Yoshiyuki Hizukuri; Kazumi Ito; Yukihiro Taira; Yasuhito Nannya; Arinobu Tojo; Toshiki Watanabe; Shinji Tsutsumi; Yutaka Suzuki; Kaoru Uchimaru
- Publisher
- Nature Publishing Group UK
- Published
- 2024
- Language
- EN
- Field
- Physics and Astronomy (Physical Sciences)