Growth factor and inflammatory signal networks are implicated in promoting cancer development, including human head and neck squamous cell carcinomas (HNSCC). The PI3K kinases important in growth signaling are implicated in modulating the reciprocal regulation of NF-kappaB/REL oncogene and TP53/63/73 family tumor suppressor function and their role in the malignant phenotype. Our findings suggest signal regulation coordinating NF-kB, TP53, p63 and p73 interactions and function may be important in pathogenesis and as targets for prevention and therapy. Genes identified as part of the Cancer Genome Atlas Network study of head and neck cancer (Nature , 2015) are implicated in NF-kappaB and cell death pathways.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. 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 TNFalpha or TRAIL, and inhibited cIAP1>XIAP>IAP2. Combination of birinapant and TNF 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 TNFalpha, 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 TNFalpha, 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.