The BH-3 mimetic venetoclax overcomes apoptosis and therapy resistance caused by high expression of BCL2 or loss of BH3-only protein function. Although a promising therapy for hematologic malignancies, increased expression of anti-apoptotic MCL-1 or BCL-XL, as well as other resistance mechanisms prevent a durable response to venetoclax. Recent studies demonstrate that agents targeting epigenetic mechanisms such as DNA methyltransferase inhibitors, histone deacetylase (HDAC) inhibitors, histone methyltransferase EZH2 inhibitors, or bromodomain reader protein inhibitors may disable oncogenic gene expression signatures responsible for venetoclax resistance. Combination therapies including venetoclax and epigenetic therapies are effective in preclinical models and the subject of many current clinical trials. Here we review epigenetic strategies to overcome venetoclax resistance mechanisms in hematologic malignancies.

BH-3 模拟 venetoclax 克服了由 BCL2 高表达或仅 BH3 蛋白功能丧失引起的细胞凋亡和治疗抗性。尽管血液系统恶性肿瘤的治疗很有前景，但抗凋亡 MCL-1 或 BCL-XL 的表达增加以及其他耐药机制阻碍了对维奈托克的持久反应。最近的研究表明，靶向表观遗传机制的药物，如 DNA 甲基转移酶抑制剂、组蛋白去乙酰化酶 (HDAC) 抑制剂、组蛋白甲基转移酶 EZH2 抑制剂或溴结构域阅读器蛋白抑制剂可能会禁用导致维奈托克耐药的致癌基因表达特征。包括 venetoclax 和表观遗传疗法在内的组合疗法在临床前模型和许多当前临床试验的主题中是有效的。