Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia.
Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia.
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DOI：
10.1038/srep27696
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发表时间：
2016-06-10
影响因子：
4.6
通讯作者：
Wood KC
中科院分区：
文献类型：
--
作者：
Lin KH;Winter PS;Xie A;Roth C;Martz CA;Stein EM;Anderson GR;Tingley JP;Wood KC
ABT-199是一种高效、选择性的bcl2小分子拮抗剂，目前正被临床用于治疗急性髓系白血病(AML)。然而，考虑到长期的单一治疗往往会产生耐药性，我们试图调查急性髓细胞白血病对ABT-199的耐药性可能产生的方式以及这些机制可能被先发制人的程度。在这里，我们使用了一种途径激活的遗传筛选来提名mcl1和bclxl作为潜在的抗性节点。然后，我们鉴定了一组通过慢性暴露于ABT-199而产生的ABT-199耐药髓系白血病细胞系，发现获得性耐药确实是由MCL-1和BCL-XL上调驱动的。通过靶向MCL-1和BCL-XL，耐药的AML细胞株可以对ABT-199重新增敏。此外，先发制人地靶向MCL-1和/或BCL-XL，同时使用ABT-199能够延迟或预防获得耐药性。总而言之，这些数据表明，在AML中，(1)初始治疗的选择动态地模版了通过调制MCL-1/BCL-XL而获得的耐药性的图景，以及(2)适当的初始治疗选择可能推迟或完全阻止对ABT-199的耐药性的获得。
ABT-199, a potent and selective small-molecule antagonist of BCL-2, is being clinically vetted as pharmacotherapy for the treatment of acute myeloid leukemia (AML). However, given that prolonged monotherapy tends to beget resistance, we sought to investigate the means by which resistance to ABT-199 might arise in AML and the extent to which those mechanisms might be preempted. Here we used a pathway-activating genetic screen to nominate MCL-1 and BCL-XL as potential nodes of resistance. We then characterized a panel of ABT-199-resistant myeloid leukemia cell lines derived through chronic exposure to ABT-199 and found that acquired drug resistance is indeed driven by the upregulation of MCL-1 and BCL-XL. By targeting MCL-1 and BCL-XL, resistant AML cell lines could be resensitized to ABT-199. Further, preemptively targeting MCL-1 and/or BCL-XL alongside administration of ABT-199 was capable of delaying or forestalling the acquisition of drug resistance. Collectively, these data suggest that in AML, (1) the selection of initial therapy dynamically templates the landscape of acquired resistance via modulation of MCL-1/BCL-XL and (2) appropriate selection of initial therapy may delay or altogether forestall the acquisition of resistance to ABT-199.