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SMAC Mimetic Birinapant plus Radiation Eradicates Human Head and Neck Cancers with Genomic Amplifications of Cell Death Genes FADD and BIRC2.
- Source :
-
Cancer research [Cancer Res] 2016 Sep 15; Vol. 76 (18), pp. 5442-5454. Date of Electronic Publication: 2016 Jul 28. - Publication Year :
- 2016
-
Abstract
- 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 about 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 blotting. 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. Cancer Res; 76(18); 5442-54. ©2016 AACR.<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- Animals
Blotting, Western
Carcinoma, Squamous Cell pathology
Cell Line, Tumor
Female
Gene Amplification
Gene Knockdown Techniques
Head and Neck Neoplasms pathology
Humans
Immunohistochemistry
Mice
Mice, Inbred BALB C
Mice, SCID
Real-Time Polymerase Chain Reaction
Squamous Cell Carcinoma of Head and Neck
TNF-Related Apoptosis-Inducing Ligand administration & dosage
Tumor Necrosis Factor-alpha administration & dosage
Xenograft Model Antitumor Assays
Antineoplastic Agents administration & dosage
Carcinoma, Squamous Cell genetics
Chemoradiotherapy methods
Dipeptides administration & dosage
Fas-Associated Death Domain Protein genetics
Head and Neck Neoplasms genetics
Indoles administration & dosage
Inhibitor of Apoptosis Proteins genetics
Ubiquitin-Protein Ligases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 76
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 27469115
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-15-3317