The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism
The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism
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DOI：
10.1182/blood-2016-01-688796
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发表时间：
2016-06-23
期刊：
影响因子：
20.3
通讯作者：
Roberts, Andrew W.
中科院分区：
文献类型：
--
作者：
Anderson, Mary Ann;Deng, Jing;Roberts, Andrew W.
Bcl2抑制线粒体途径的激活，导致细胞凋亡，而高水平的表达是慢性淋巴细胞白血病(CLL)生存所必需的。VENTOCLAX(ABT-199)是一种bcl2的小分子选择性抑制剂，目前正在进行CLL和其他恶性肿瘤的临床试验。结合万乃馨治疗复发或难治性CLL患者(M12-175)的第一期人类临床试验，我们研究了万乃馨在体内的作用机制，探索了体外敏感性分析或BH3图谱与患者体内反应的相关性，并确定了TP53功能丧失是否会影响体外和体内的反应。在所有被测试的样品中，万乃馨在体外以体内可达到的浓度诱导CLL细胞死亡，细胞死亡在4小时内明显。一些患者在单次20 mg或50 mg剂量后6或24小时在体内检测到凋亡的CLL细胞。BIM BH3多肽在体外对线粒体去极化的程度与体内血液和骨髓中CLL的减少百分比有关，而标准细胞毒性试验得出的半数致死浓度与此无关。CLL细胞的体外死亡和临床反应的深度与染色体17p缺失、TP53突变和TP53功能无关。这些数据提供了直接的证据，表明ventoclax通过抑制患者的BCL2以TP53非依赖的方式杀死CLL细胞，并支持进一步评估BH3特征作为该药物的预测生物标志物。
BCL2 blunts activation of the mitochondrial pathway to apoptosis, and high-level expression is required for chronic lymphocytic leukemia (CLL) survival. Venetoclax (ABT-199) is a small-molecule selective inhibitor of BCL2 currently in clinical trials for CLL and other malignancies. In conjunction with the phase 1 first-in-human clinical trial of venetoclax in patients with relapsed or refractory CLL (M12-175), we investigated the mechanism of action of venetoclax in vivo, explored whether in vitro sensitivity assays or BH3 profiling correlated with in vivo responses in patients, and determined whether loss of TP53 function affected responses in vitro and in vivo. In all samples tested, venetoclax induced death of CLL cells in vitro at concentrations achievable in vivo, with cell death evident within 4 hours. Apoptotic CLL cells were detected in vivo 6 or 24 hours after a single 20-mg or 50-mg dose in some patients. The extent of mitochondrial depolarization by a BIM BH3 peptide in vitro was correlated with percentage reduction of CLL in the blood and bone marrow in vivo, whereas the half lethal concentration derived from standard cytotoxicity assays was not. CLL cell death in vitro and the depth of clinical responses were independent of deletion of chromosome 17p, TP53 mutation, and TP53 function. These data provide direct evidence that venetoclax kills CLL cells in a TP53-independent fashion by inhibition of BCL2 in patients and support further assessment of BH3 profiling as a predictive biomarker for this drug.