Mechanisms of action and resistance in histone methylation-targeted therapy

• 成果类型: Article
• 署名作者: Yamagishi, Makoto; Kuze, Yuta; Kobayashi, Seiichiro; Nakashima, Makoto; Morishima, Satoko; Kawamata, Toyotaka; Makiyama, Junya; Suzuki, Kako; Seki, Masahide; Abe, Kazumi; Imamura, Kiyomi; Watanabe, Eri; Tsuchiya, Kazumi; Yasumatsu, Isao; Takayama, Gensuke; Hizukuri, Yoshiyuki; Ito, Kazumi; Taira, Yukihiro; Nannya, Yasuhito; Tojo, Arinobu; Watanabe, Toshiki; Tsutsumi, Shinji; Suzuki, Yutaka; Uchimaru, Kaoru
• 署名单位: University of Tokyo; University of Tokyo; University of Tokyo; University of Tokyo; University of the Ryukyus; University of Tokyo; University of Tokyo; Daiichi Sankyo Company Limited; Daiichi Sankyo Company Limited; Institute of Science Tokyo; Tokyo Medical & Dental University (TMDU); Saint Marianna University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6637
• DOI: 10.1038/s41586-024-07103-x
• 发表日期: 2024-03-07
• 页码: 221-+
• 关键词: t-cell leukemia; h3 lysine 27; point mutations; web server; open-label; ezh2; expression; chromatin; tazemetostat; inhibitor

摘要

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 result in the propagation of clones with increased H3K27me3 expression. In patients free of PRC2 mutations, TET2 mutation or elevated DNMT3A expression causes similar chromatin recondensation through de novo DNA methylation in the H3K27me3-associated regions. We identified subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations. Targeting epigenetic drivers and chromatin homeostasis may provide opportunities for further sustained epigenetic cancer therapies.