软组织肉瘤（STS）是罕见的间充质恶性肿瘤，具有独特的分子、组织学和临床特征。许多STS通常被认为是表观遗传疾病，因为存在染色质紊乱。发现染色质重塑BRG1/BRM相关复合物（BAFs）与组蛋白修饰多能抑制复合物（PRCs）之间的功能对抗失调，提供了新的可行靶点。在上皮样肉瘤（ES）、颅外、肾外恶性病毒性软组织肿瘤（eMRTs）和滑膜肉瘤（SS）中，由于不同的改变引起的BAF核心亚单位SMARCB1的全部或部分丧失与PRC2失调及其酶亚单位EZH2的依赖性相关。在这些SMARCB1缺陷的STS中，异常的EZH2表达和/或活性成为一种可治疗的脆弱点。尽管临床前研究支持EZH2的靶向治疗作为一种有希望的治疗选项，但临床研究显示对EZH2抑制剂的反应不一致。实际上，虽然ES患者的临床益处促使FDA批准了EZH2抑制剂Tazemetostat，但在eMRT和SS患者中观察到的有限和零星的反应突显了加深机制以及药理学研究以提高药物效果的需求。我们总结了ES、eMRT和SS中驱动SMARCB1缺陷和EZH2失调的不同机制的当前知识，以及EZH2靶向药物的临床前和临床研究。将讨论EZH2及其同源物EZH1在反应抗EZH2药物中的PRC2-和酶相关-independent功能以及正在研究的联合策略的可能影响，以改善这些肿瘤的EZH2靶向治疗的疗效。版权所有© 2023 Elsevier Inc. 保留所有权利。

Soft tissue sarcomas (STSs) are rare mesechymal malignancies characterized by distintive molecular, histological and clinical features. Many STSs are considered as predominatly epigenetic diseases due to underlying chromatin deregulation. Discovery of deregulated functional antagonism between the chromatin remodeling BRG1/BRM-associated (BAFs) and the histone modifying Polycomb repressor complexes (PRCs) has provided novel actionable targets. In epithelioid sarcoma (ES), extracranial, extrarenal malignant rhabdoid tumors (eMRTs) and synovial sarcoma (SS), the total or partial loss of the BAF core subunit SMARCB1, driven by different alterations, is associated with PRC2 deregulation and dependency on its enzymatic subunit, EZH2. In these SMARCB1-deficient STSs, aberrant EZH2 expression and/or activity emerged as a druggable vulnerability. Although preclinical investigation supported EZH2 targeting as a promising therapeutic option, clinical studies demonstrated a variable response to EZH2 inhibitors. Actually, whereas the clinical benefit recorded in ES patients prompted the FDA approval of the EZH2 inhibitor tazemetostat, the modest and sporadic responses observed in eMRT and SS patients highlighted the need to deepen mechanistic as well as pharmacological investigations to improve drug effectiveness. We summarize the current knowledge of different mechanisms driving SMARCB1 deficiency and EZH2 deregulation in ES, eMRT and SS along with preclinical and clinical studies of EZH2-targeting agents. Possible implication of the PRC2- and enzymatic-independent functions of EZH2 and of its homolog, EZH1, in the response to anti-EZH2 agents will be discussed together with combinatorial strategies under investigation to improve the efficacy of EZH2 targeting in these tumors.Copyright © 2023 Elsevier Inc. All rights reserved.