Activation of concurrent apoptosis and necroptosis by SMAC mimetics for the treatment of refractory and relapsed ALL
Activation of concurrent apoptosis and necroptosis by SMAC mimetics for the treatment of refractory and relapsed ALL
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DOI：
10.1126/scitranslmed.aad2986
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发表时间：
2016-05-18
影响因子：
17.1
通讯作者：
Bornhauser, Beat C.
中科院分区：
文献类型：
--
作者：
McComb, Scott;Aguade-Gorgorio, Julia;Bornhauser, Beat C.
迫切需要更精确的治疗策略来降低毒性并改善难治性白血病的结局。我们使用了高风险、复发或难治性急性淋巴细胞白血病（ALL）病例的体外药物反应谱，并确定了对第二种胱天蛋白酶激活剂（SMAC）蛋白的小分子模拟物具有极高敏感性的亚组。SMAC模拟物（SM）birinapant的有效离体活性与显著的体内抗白血病作用相关，如移植延迟、白血病负荷降低和异种移植小鼠存活延长所示。抗白血病活性依赖于细胞凋亡和坏死性凋亡的同时执行，如通过使用多色lentiCRISPR方法同时破坏患者源性ALL中的多个基因的功能性基因组解剖所证明的。SM特异性靶向受体相互作用蛋白激酶1（RIP1）依赖性死亡，CRISPR介导的RIP1破坏完全阻断了SM诱导的死亡，但对标准抗白血病药物的反应没有影响。因此，SM化合物如birinapant通过激活有效的双重RIP1依赖性细胞凋亡和坏死性细胞死亡来避免白血病细胞凋亡的逃逸，这在目前的治疗中没有被利用。离体药物活性分析可以提供重要的功能诊断信息，以确定在早期临床试验中可能受益于birinapant靶向治疗的患者。
More precise treatment strategies are urgently needed to decrease toxicity and improve outcomes for treatment-refractory leukemia. We used ex vivo drug response profiling of high-risk, relapsed, or refractory acute lymphoblastic leukemia (ALL) cases and identified a subset with exquisite sensitivity to small-molecule mimetics of the second mitochondria-derived activator of caspases (SMAC) protein. Potent ex vivo activity of the SMAC mimetic (SM) birinapant correlated with marked in vivo antileukemic effects, as indicated by delayed engraftment, decreased leukemia burden, and prolonged survival of xenografted mice. Antileukemic activity was dependent on simultaneous execution of apoptosis and necroptosis, as demonstrated by functional genomic dissection with a multicolored lentiCRISPR approach to simultaneously disrupt multiple genes in patient-derived ALL. SM specifically targeted receptor-interacting protein kinase 1 (RIP1)-dependent death, and CRISPR-mediated disruption of RIP1 completely blocked SM-induced death yet had no impact on the response to standard antileukemic agents. Thus, SM compounds such as birinapant circumvent escape from apoptosis in leukemia by activating a potent dual RIP1-dependent apoptotic and necroptotic cell death, which is not exploited by current therapy. Ex vivo drug activity profiling could provide important functional diagnostic information to identify patients who may benefit from targeted treatment with birinapant in early clinical trials.