Dexamethasone treatment promotes Bcl-2 dependence in multiple myeloma resulting in sensitivity to venetoclax.
Dexamethasone treatment promotes Bcl-2 dependence in multiple myeloma resulting in sensitivity to venetoclax.
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DOI：
10.1038/leu.2015.350
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发表时间：
2016-05
期刊：
影响因子：
11.4
通讯作者：
Boise LH
中科院分区：
文献类型：
--
作者：
Matulis SM;Gupta VA;Nooka AK;Hollen HV;Kaufman JL;Lonial S;Boise LH
维奈托克（ABT-199）是抗凋亡蛋白Bcl-2的特异性抑制剂，目前正处于多发性骨髓瘤的I期临床试验中。结果表明，维奈托克仅在一小群患者中有效，因此我们希望确定其联合使用时的疗效。联合使用维奈托克与美法仑或卡非佐米，在5个测试细胞系中的4个中产生了相加或更好的细胞死亡。最引人注目的结果是地塞米松。在5种细胞系中的4种细胞系和所有检测的患者样本中，与单独使用维奈托克相比，地塞米松和维奈托克共同处理人骨髓瘤细胞系和原代患者样本显著增加了细胞死亡。发生这种情况的机制是加入地塞米松后Bcl-2和Bim的表达增加。这导致Bim与抗凋亡蛋白结合的改变。地塞米松使Bim结合向Bcl-2转移，导致对维奈托克的敏感性增加。这些数据表明，药物诱导的Bim结合模式的改变的知识可能有助于更好地联合用药方案。此外，数据表明，将这种新型治疗剂与地塞米松结合可能是一种有效的治疗方法，适用于比单药活性预测更广泛的患者。
Venetoclax (ABT-199), a specific inhibitor of the anti-apoptotic protein Bcl-2, is currently in phase I clinical trials for multiple myeloma. Results suggest that venetoclax is only active in a small cohort of patients therefore we wanted to determine its efficacy when used in combination. Combining venetoclax with melphalan or carfilzomib produced additive or better cell death in 4 of the 5 cell lines tested. The most striking results were seen with dexamethasone. Co-treatment of human myeloma cell lines and primary patient samples, with dexamethasone and venetoclax significantly increased cell death over venetoclax alone in 4 of the 5 cell lines, and in all patient samples tested. The mechanism by which this occurs is an increase in the expression of both Bcl-2 and Bim upon addition of dexamethasone. This results in alterations in Bim binding to anti-apoptotic proteins. Dexamethasone shifts Bim binding towards Bcl-2 resulting in increased sensitivity to venetoclax. These data suggest that knowledge of drug-induced alterations of Bim binding patterns may help inform better combination drug regimens. Furthermore, the data indicate combining this novel therapeutic with dexamethasone could be an effective therapy for a broader range of patients than would be predicted by single agent activity.