文章：

BET蛋白抑制剂与BCL2或MCL1抑制剂联合治疗对AML原始祖细胞的显著疗效

Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells

原文发布日期：2019-01-15

DOI: 10.1038/s41408-018-0165-5

类型: Article

开放获取: 是

英文摘要：

First-generation bromodomain extra-terminal protein (BETP) inhibitors (BETi) (e.g., OTX015) that disrupt binding of BETP BRD4 to chromatin transcriptionally attenuate AML-relevant progrowth and prosurvival oncoproteins. BETi treatment induces apoptosis of AML BPCs, reduces in vivo AML burden and induces clinical remissions in a minority of AML patients. Clinical efficacy of more potent BETis, e.g., ABBV-075 (AbbVie, Inc.), is being evaluated. Venetoclax and A-1210477 bind and inhibit the antiapoptotic activity of BCL2 and MCL1, respectively, lowering the threshold for apoptosis. BETi treatment is shown here to perturb accessible chromatin and activity of enhancers/promoters, attenuating MYC, CDK6, MCL1 and BCL2, while inducing BIM, HEXIM1, CDKN1A expressions and apoptosis of AML cells. Treatment with venetoclax increased MCL1 protein levels, but cotreatment with ABBV-075 reduced MCL1 and Bcl-xL levels. ABBV-075 cotreatment synergistically induced apoptosis with venetoclax or A-1210477 in patient-derived, CD34+ AML cells. Compared to treatment with either agent alone, cotreatment with ABBV-075 and venetoclax was significantly more effective in reducing AML cell-burden and improving survival, without inducing toxicity, in AML-engrafted immune-depleted mice. These findings highlight the basis of superior activity and support interrogation of clinical efficacy and safety of cotreatment with BETi and BCL2 or MCL1 inhibitor in AML.

摘要翻译： 

第一代溴结构域末端外蛋白(BETP)抑制剂(如OTX015)通过破坏BETP BRD4与染色质的结合，在转录水平上抑制急性髓系白血病相关的促生长和促生存癌蛋白。BET抑制剂治疗可诱导AML原始细胞的凋亡，降低体内AML负荷，并在少数AML患者中诱导临床缓解。目前正在评估更强效BET抑制剂（如艾伯维公司的ABBV-075）的临床疗效。维奈托克和A-1210477分别结合并抑制BCL2和MCL1的抗凋亡活性，从而降低细胞凋亡阈值。本研究表明，BET抑制剂处理可扰动易接近染色质及增强子/启动子活性，在减弱MYC、CDK6、MCL1和BCL2表达的同时，诱导BIM、HEXIM1、CDKN1A的表达并引发AML细胞凋亡。维奈托克单药治疗会升高MCL1蛋白水平，但与ABBV-075联用可降低MCL1和Bcl-xL水平。在患者来源的CD34阳性AML细胞中，ABBV-075与维奈托克或A-1210477联用可协同诱导凋亡。在AML移植的免疫缺陷小鼠模型中，与单药治疗相比，ABBV-075与维奈托克联合疗法在降低AML细胞负荷和提高生存率方面显著更有效，且未诱发毒性反应。这些发现揭示了联合治疗的优越活性基础，并为在AML中临床验证BET抑制剂与BCL2或MCL1抑制剂联合治疗的疗效和安全性提供理论依据。

原文链接：

Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells