近日，日本东京大学Kaoru Uchimaru等研究人员合作揭示组蛋白甲基化靶向疗法的作用机制和抗药性。该项研究成果于2024年2月21日在线发表在《自然》杂志上。

研究人员展示了EZH1-EZH2双重抑制剂伐美妥司他在成人T细胞白血病/淋巴瘤患者临床试验中的效力、作用机制和耐药性。在具有多种基因突变的侵袭性淋巴瘤中，服用伐美妥司他可缩小肿瘤体积，并显示出持久的临床反应。单细胞综合分析表明，伐美妥司他能消除由可塑性H3K27me3形成的高度凝聚的染色质结构，并中和多个基因位点，包括肿瘤抑制基因。然而，在随后的长期治疗中会出现耐药克隆，其重建的聚合染色质与用药前的状态非常相似。PRC2-化合物界面上的后天突变导致H3K27me3表达增加的克隆繁殖。

在没有PRC2突变的患者中，TET2突变或DNMT3A表达的升高会通过H3K27me3相关区域的从头DNA甲基化导致类似的染色质重组。研究人员确定了具有不同代谢和基因翻译特征的亚群，这些特征与获得遗传（表观）突变之前的原发性易感性有关。以表观遗传驱动因素和染色质稳态为靶点，可为进一步的持续表观遗传癌症疗法提供机会。

据介绍，表观基因组可纠正紊乱的癌症基因表达，从而为药物干预提供新的靶点。组蛋白H3赖氨酸三甲基化（H3K27me3）是一种表观遗传标志，其靶向治疗的临床效用已得到证实。然而，在实际治疗中，H3K27me3靶向疗法的作用机制和肿瘤细胞的反应仍不清楚。

附：英文原文

Title: Mechanisms of action and resistance in histone methylation-targeted therapy

Author: 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

Issue&Volume: 2024-02-21

Abstract: 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 demonstrated1,2,3,4,5,6,7. 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.

DOI: 10.1038/s41586-024-07103-x

Source: https://www.nature.com/articles/s41586-024-07103-x