Abstract 1724: Integrated functional RNAi screening and structural genomics identify inverse co-modulators of TP53 family and NF-{kappa}B transitional activation as potential therapeutic targets in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide with a 50-60% mortality rate. Deregulation of p53 family members in HNSCC occurs in over 90% of cases, preventing transcription of growth arrest and apoptosis genes. Conversely, members of the NF-κB/REL family are aberrantly activated in about ∼70% of cases, and drive expression of pro-proliferation, inflammation, angiogenesis, and therapeutic resistance genes. The function of different TP53 and NF-κB family members are inversely modulated within two major subsets of HNSCC, suggesting that common molecules and pathways coordinate this modulation. To test this hypothesis, we have developed HNSCC stable cell lines that report transcriptional activation of TP53 or NF-κB individually through a β-lactamase reporter. Whole genome siRNA screening in our NF-κB reporter cell line has been performed. Screening was performed by 56-hour knockdown with siRNAs, followed by stimulation with TNF-α. The results have revealed known and novel targets that maintain oncogenic NF-κB signaling in HNSCC. Validating the assay, most structural components of the TNF receptor complex and downstream NF-κB pathway genes, such as IKKs, scored highly in the screen. We integrated this functional genomics data with structural mutation and expression data from TCGA to prioritize genes that are frequently deregulated in HNSCC specimens from patients. Several co-receptors that may support NF-κB signaling were identif...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Experimental and Molecular Therapeutics Source Type: research