SMAC Mimetics Synergistically Cooperate with HDAC Inhibitors Enhancing TNF-α Autocrine Signaling.
SMAC Mimetics Synergistically Cooperate with HDAC Inhibitors Enhancing TNF-α Autocrine Signaling.
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SMAC Mimetics与HDAC抑制剂协同合作，增强TNF-α自分泌信号传导。
作者：
SMAC 模拟物与 HDAC 抑制剂的组合是一种新颖且有前途的癌症治疗策略。 HDAC 抑制剂通过刺激自分泌 TNF-α 的产生，与 SMAC 模拟物产生机械协同作用。细胞凋亡抑制剂 (IAP) 蛋白的过度表达与卵巢癌女性的不良生存密切相关。复发性卵巢癌由于 IAP 蛋白失调而抵抗细胞凋亡。从机制上讲，第二线粒体半胱天冬酶激活剂 (SMAC) 模拟物抑制 IAP 蛋白的功能，恢复细胞凋亡途径，导致肿瘤死亡。我们之前对单药 SMAC 模拟 birinapant 进行了 2 期临床试验，并观察到尽管显示出靶向活性，但在患有复发性卵巢癌的女性中药物反应极小。因此，我们进行了高通量筛选矩阵来鉴定与 birinapant 的协同药物组合。 SMAC 模拟物与 HDAC 抑制剂组合显示出显着的协同作用，因此被选择进行进一步评估。我们在此表明，在体外和体内观察到的这种协同作用是多种汇聚途径的结果，包括 caspase 激活增加、HDAC 抑制剂介导的 TNF-α 上调和替代 NF-kB 信号传导。这些发现为在治疗选择仍然有限的复发性卵巢癌临床试验中整合 SMAC 模拟物和 HDAC 抑制剂提供了理论依据。
The combination of a SMAC mimetic with an HDAC inhibitor is a novel and promising strategy for cancer treatment. The HDAC inhibitor mechanistically synergizes with SMAC mimetics by stimulating autocrine TNF-α production. The overexpression of inhibitor of apoptosis (IAP) proteins is strongly related to poor survival of women with ovarian cancer. Recurrent ovarian cancers resist apoptosis due to the dysregulation of IAP proteins. Mechanistically, Second Mitochondrial Activator of Caspases (SMAC) mimetics suppress the functions of IAP proteins to restore apoptotic pathways resulting in tumor death. We previously conducted a phase 2 clinical trial of the single-agent SMAC mimetic birinapant and observed minimal drug response in women with recurrent ovarian cancer despite demonstrating on-target activity. Accordingly, we performed a high-throughput screening matrix to identify synergistic drug combinations with birinapant. SMAC mimetics in combination with an HDAC inhibitor showed remarkable synergy and was, therefore, selected for further evaluation. We show here that this synergy observed both in vitro and in vivo results from multiple convergent pathways to include increased caspase activation, HDAC inhibitor-mediated TNF-α upregulation, and alternative NF-kB signaling. These findings provide a rationale for the integration of SMAC mimetics and HDAC inhibitors in clinical trials for recurrent ovarian cancer where treatment options are still limited.
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64.5
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