Signal and Transcription Factor Network interactions in Head and Neck Cancer

National Institute On Deafness And Other Communication Disorders

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Abstract

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. In vivo, birinapant inhibited tumor growth and enhanced radiation induced TNFalpha, tumor responses, and host survival in xenograft models. 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. A study of birinapant plus re-irradiation is ongoing. Recent collaborative studies on TRAIL agonist, HSP90 inhibitors, and the tumor suppressor FAT1 have been competed