University of Florida Health Cancer Center and University of Florida Department of Medicine, Division of Hematology and Oncology, Gainesville, FL 32610, United States of America.
University of Florida Health Cancer Center and University of Florida Department of Medicine, Division of Hematology and Oncology, Gainesville, FL 32610, United States of America.
Biochim Biophys Acta Mol Cell Res. 2021 Jul;1868(8):119047. doi: 10.1016/j.bbamcr.2021.119047. Epub 2021 May 1.
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 模拟物 venetoclax 克服了由于 BCL2 高表达或 BH3 仅有蛋白功能缺失引起的细胞凋亡和治疗抵抗。尽管这是一种有前途的血液系统恶性肿瘤治疗方法，但抗凋亡 MCL-1 或 BCL-XL 的表达增加，以及其他耐药机制，阻止了对 venetoclax 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 抑制剂或溴结构域读取蛋白抑制剂，可能会使导致 venetoclax 耐药的致癌基因表达特征失活。包括 venetoclax 和表观遗传疗法在内的联合疗法在临床前模型中是有效的，也是许多当前临床试验的主题。在这里，我们综述了克服血液系统恶性肿瘤中 venetoclax 耐药机制的表观遗传策略。
