SMAC Mimetic Birinapant plus Radiation Eradicates Human Head and Neck Cancers with Genomic Amplifications of Cell Death Genes FADD and BIRC2.
SMAC Mimetic Birinapant plus Radiation Eradicates Human Head and Neck Cancers with Genomic Amplifications of Cell Death Genes FADD and BIRC2.
复制标题
DOI：
10.1158/0008-5472.can-15-3317
复制
发表时间：
2016-09-15
期刊：
影响因子：
11.2
通讯作者：
Van Waes C
中科院分区：
文献类型：
--
作者：
Eytan DF;Snow GE;Carlson S;Derakhshan A;Saleh A;Schiltz S;Cheng H;Mohan S;Cornelius S;Coupar J;Sowers AL;Hernandez L;Mitchell JB;Annunziata CM;Chen Z;Van Waes C
癌症基因组图谱（TCGA）中肿瘤的比较显示，头颈部鳞状细胞癌（HNSCC）具有最常见的Fas相关死亡结构域（FADD）基因组扩增，伴或不伴含BIRC 2（cIAP 1）的杆状病毒凋亡抑制剂重复序列，影响约30%的患者，预后较差。在此，我们通过外显子组测序、RT-PCR和Western印迹鉴定了具有FADD/BIRC 2扩增和过表达的HNSCC细胞系。在体外，FADD或BIRC 2 siRNA敲低抑制HNSCC展示扩增和增加这些基因的表达，支持它们在促进增殖中的功能重要性。Birinapant是一种新型SMAC模拟物，通过激动剂TNFα或TRAIL使多种HNSCC细胞系对细胞死亡敏感，并抑制cIAP 1>XIAP> IAP 2。birinapant和TNFα联合诱导敏感细胞系中的亚G 0 DNA片段化，birinapant单独也诱导UM-SCC-46细胞中显著的G2/M细胞周期停滞和细胞死亡。FADD致敏耐药UM-SCC-38细胞的基因转移和表达缺乏对birinapant和TNFα的FADD扩增，支持FADD在对IAP抑制剂和死亡配体致敏中的作用。HNSCC的细胞死亡机制各不相同，如半胱天冬酶依赖性细胞凋亡和/或RIPK 1/MLKL介导的坏死性凋亡的抑制剂或蛋白标志物逆转所示。在体内，birinapant在显示FADD+/− BIRC 2扩增和过表达的UM-SCC-46和-11B异种移植模型中抑制肿瘤生长并增强辐射诱导的TNFα、肿瘤反应和宿主存活。这些发现表明，SMAC模拟物如birinapant加辐射的组合可能在HNSCC中特别有效，HNSCC具有频繁的FADD/BIRC 2基因组改变。
Comparison of tumors from the Cancer Genome Atlas (TCGA) reveals that head and neck squamous cell carcinomas (HNSCC) harbor the most frequent genomic amplifications of Fas-associated death domain (FADD), with or without Baculovirus Inhibitor of Apoptosis repeat containing BIRC2 (cIAP1), affecting ~30% of patients in association with worse prognosis. Here, we identified HNSCC cell lines harboring FADD/BIRC2 amplifications and overexpression by exome sequencing, RT-PCR and Western blot. In vitro, FADD or BIRC2 siRNA knockdown inhibited HNSCC displaying amplification and increased expression of these genes, supporting their functional importance in promoting proliferation. Birinapant, a novel SMAC mimetic, sensitized multiple HNSCC lines to cell death by agonists TNFα or TRAIL, and inhibited cIAP1>XIAP>IAP2. Combination of birinapant and TNFα induced sub-G0 DNA fragmentation in sensitive lines, and birinapant alone also induced significant G2/M cell cycle arrest and cell death in UM-SCC-46 cells. Gene transfer and expression of FADD sensitized resistant UM-SCC-38 cells lacking FADD amplification to birinapant and TNFα, supporting a role for FADD in sensitization to IAP inhibitor and death ligands. HNSCC varied in mechanisms of cell death, as indicated by reversal by inhibitors or protein markers of caspase-dependent apoptosis and/or RIPK1/MLKL-mediated necroptosis. In vivo, birinapant inhibited tumor growth and enhanced radiation induced TNFα, tumor responses, and host survival in UM-SCC-46 and -11B xenograft models displaying amplification and overexpression of FADD+/−BIRC2. These findings suggest that combination of SMAC mimetics such as birinapant plus radiation may be particularly active in HNSCC, which harbor frequent FADD/BIRC2 genomic alterations.