Derakhshan Adeeb, Chen Zhong, Van Waes Carter
Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland.
Clin Cancer Res. 2017 Mar 15;23(6):1379-1387. doi: 10.1158/1078-0432.CCR-16-2172. Epub 2016 Dec 30.
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 (IAP) that complex with members of the TNF receptor family. Second mitochondria-derived activator of caspases (SMAC) mimetics, modeled after the endogenous IAP antagonist SMAC, and IAP inhibitors represent important classes of novel small molecules currently in phase I/II clinical trials. Here we review the physiologic roles of IAPs, FADD, and other components involved in cell death, cell 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 , whereas their antitumor effects were augmented when combined with radiation and chemotherapeutic agents that induce TNFα 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. .
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各组分的基因组失调情况。这种改变在头颈部鳞状细胞癌（HNSCC）中尤为常见，该癌症常常表现出与肿瘤坏死因子受体家族成员相互作用的死亡结构域相关蛋白（FADD）和凋亡抑制蛋白（IAP）的扩增和过表达。以内源性IAP拮抗剂SMAC为蓝本设计的第二线粒体来源的半胱天冬酶激活剂（SMAC）模拟物以及IAP抑制剂，是目前正处于I/II期临床试验阶段的重要新型小分子类别。在此，我们综述IAP、FADD以及其他参与癌症（包括HNSCC）细胞死亡、细胞存活和核因子κB信号通路的组分的生理作用。我们总结了在HNSCC临床前模型中使用SMAC模拟物靶向IAP的结果。SMAC模拟物与死亡激动剂肿瘤坏死因子α（TNFα）或肿瘤坏死因子相关凋亡诱导配体（TRAIL）具有协同活性，而当它们与诱导TNFα的放疗和化疗药物联合使用时，其抗肿瘤作用会增强。此外，还总结了在HNSCC和实体瘤患者中测试SMAC模拟物作为单一药物或与化疗或放疗联合使用的临床试验情况。随着我们对不同癌症中失调的死亡和存活途径背后的基因组改变和分子机制有更深入的了解，SMAC模拟物和IAP抑制剂在癌症治疗中的作用将得以阐明。此类进展可能会提高精准治疗水平并改善癌症患者的治疗效果。
