Mitochondrial Bcl-2 Family Dynamics Define Therapy Response and Resistance in Neuroblastoma
Mitochondrial Bcl-2 Family Dynamics Define Therapy Response and Resistance in Neuroblastoma
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DOI：
10.1158/0008-5472.can-11-3603
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发表时间：
2012-05-15
期刊：
影响因子：
11.2
通讯作者：
Hogarty, Michael D.
中科院分区：
文献类型：
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作者：
Goldsmith, Kelly C.;Gross, Michelle;Hogarty, Michael D.
神经母细胞瘤是一种儿童肿瘤，其中短暂的治疗反应通常伴随着致命的化疗耐药疾病的复发。在这项研究中，我们的特点是在不同的神经母细胞瘤的凋亡反应，使用无偏的线粒体功能测定。我们使用对不同BH 3死亡结构域的反应来定义神经母细胞瘤的凋亡设定点，从而提供BH 3反应谱并直接确认生存依赖性。我们发现，活的神经母细胞瘤细胞和原发性肿瘤的死亡准备与紧张性螯合的Bim，细胞凋亡的直接激活剂，由Bcl-2或Mcl-1，提供生存依赖性，预测Bcl-2拮抗剂的活性。Bcl-2/Bcl-xL/Bcl-w抑制剂ABT-737仅对Bim：Bcl-2致敏的肿瘤异种移植物显示出单药活性。即使对于MYCN扩增和激活ALK突变的最高风险分子亚型，联合非治愈性化疗也可实现持久的完全消退。此外，在诊断时和复发时使用来自患者的独特等基因细胞系表明，治疗抗性不是由Bcl-2同源物的上调或Bim引发的丧失介导的，而是由受抑制的巴克/Bax活化介导的。总之，我们的研究结果提供了一个分类系统，确定肿瘤与Bcl-2拮抗剂的临床反应，定义Mcl-1作为Bcl-2拮抗剂耐药诊断的主要介质，并隔离治疗耐药表型的线粒体。Cancer Res; 72（10）; 2565-77. (C)2012年AACR。
Neuroblastoma is a childhood tumor in which transient therapeutic responses are typically followed by recurrence with lethal chemoresistant disease. In this study, we characterized the apoptotic responses in diverse neuroblastomas using an unbiased mitochondrial functional assay. We defined the apoptotic set point of neuroblastomas using responses to distinct BH3 death domains providing a BH3 response profile and directly confirmed survival dependencies. We found that viable neuroblastoma cells and primary tumors are primed for death with tonic sequestration of Bim, a direct activator of apoptosis, by either Bcl-2 or Mcl-1, providing a survival dependency that predicts the activity of Bcl-2 antagonists. The Bcl-2/Bcl-xL/Bcl-w inhibitor ABT-737 showed single-agent activity against only Bim: Bcl-2 primed tumor xenografts. Durable complete regressions were achieved in combination with noncurative chemotherapy even for highest risk molecular subtypes with MYCN amplification and activating ALK mutations. Furthermore, the use of unique isogenic cell lines from patients at diagnosis and at the time of relapse showed that therapy resistance was not mediated by upregulation of Bcl-2 homologues or loss of Bim priming, but by repressed Bak/Bax activation. Together, our findings provide a classification system that identifies tumors with clinical responses to Bcl-2 antagonists, defines Mcl-1 as the principal mediator of Bcl-2 antagonist resistance at diagnosis, and isolates the therapy resistant phenotype to the mitochondria. Cancer Res; 72(10); 2565-77. (C) 2012 AACR.