Therapeutic Small Molecules Target Inhibitor of Apoptosis Proteins in Cancers with Deregulation of Extrinsic and Intrinsic Cell Death Pathways.
Therapeutic Small Molecules Target Inhibitor of Apoptosis Proteins in Cancers with Deregulation of Extrinsic and Intrinsic Cell Death Pathways.
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DOI：
10.1158/1078-0432.ccr-16-2172
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发表时间：
2017-03-15
期刊：
影响因子：
--
通讯作者：
Van Waes C
中科院分区：
文献类型：
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作者：
Derakhshan A;Chen Z;Van Waes C
癌症基因组图谱（TCGA）揭示了不同类型癌症中外源性和内源性凋亡途径的各种组分的基因组失调。这种改变在头颈部鳞状细胞癌（HNSCC）中特别常见，其经常显示与肿瘤坏死因子（TNF）受体家族成员复合的Fas相关的死亡结构域（FADD）和凋亡抑制蛋白（IAP）的扩增和过表达。SMAC模拟物，模仿内源性IAP拮抗剂的第二个来源于半胱天冬酶的激活剂（SMAC），和IAP抑制剂，代表了目前在I/II期临床试验的新型小分子的重要类别。在此，我们回顾了IAP、FADD和其他参与细胞死亡、存活和NF-κB信号通路在癌症（包括HNSCC）中的生理作用。我们总结了使用SMAC模拟物在HNSCC临床前模型中靶向IAP的结果。SMAC模拟物与死亡激动剂TNFα或TRAIL一起在体外发生协同活性，而当与体内诱导TNFα的放射和化疗剂组合时，其抗肿瘤作用增强。此外，总结了在HNSCC和实体瘤患者中测试SMAC模拟物作为单一药剂或与化疗或放疗一起的临床试验。随着我们对不同癌症中失调死亡和存活途径的基因组改变和分子机制的深入了解，SMAC模拟物和IAP抑制剂在癌症治疗中的作用将得到阐明。这些发展可以增强精确治疗并改善癌症患者的结果。
The Cancer Genome Atlas (TCGA) has unveiled genomic deregulation of various components of the extrinsic and intrinsic apoptotic pathways in different types of cancers. Such alterations are particularly common in head and neck squamous cell carcinomas (HNSCC), which frequently display amplification and overexpression of the Fas-associated via death domain (FADD) and inhibitor of apoptosis proteins (IAPs), that complex with members of the tumor necrosis factor (TNF) receptor family. SMAC mimetics, modeled after the endogenous IAP antagonist second mitochondria-derived activator of caspases (SMAC), and IAP inhibitors, represent important classes of novel small-molecules currently in phase I/II clinical trials. Here we review the physiological roles of IAPs, FADD, and other components involved in cell death, survival, and NF-κB signaling pathways in cancers, including HNSCC. We summarize the results of targeting IAPs in preclinical models of HNSCC using SMAC mimetics. Synergistic activity of SMAC mimetics together with death agonists TNFα or TRAIL occurred in vitro, while their anti-tumor effects were augmented when combined with radiation and chemotherapeutic agents that induce TNFα in vivo. In addition, clinical trials testing SMAC mimetics as single agents or together with chemo- or radiation therapies in patients with HNSCC and solid tumors are summarized. As we achieve a deeper understanding of the genomic alterations and molecular mechanisms underlying deregulated death and survival pathways in different cancers, the role of SMAC mimetics and IAP inhibitors in cancer treatment will be elucidated. Such developments could enhance precision therapeutics and improve outcomes for cancer patients.