Abstract C70: Integrative analysis of pharmacologic, genomic, and transcriptomic assays in cancer

We describe an integrative analysis approach leveraging the publicly available Cancer Cell Line Encyclopedia to uncover regulatory pathways in cancer. Six different lines of evidence are considered in identifying candidate factors associated with disease: 1) gene mutation status, 2) copy number variations, 3) RNAi growth inhibitions, 4) pharmacological growth inhibitions, 5) baseline gene expression data, and 6) physical protein-protein interactions. As each of these evidence sources measure a different aspect of cellular regulation, they may be considered in combination to uncover regulatory mechanisms associated with tumorigenesis. For example, gene mutation status or copy number variation data may be combined with baseline gene expressions to identify genes that are differentially expressed in cell lines with aberrant or deactivated versions of specific tumor suppressors and oncogenes. To assess our approach, we applied it to identification of genes involved in the well-known RAS-RAF regulatory signaling pathway in both tissuespecific and nonspecific contexts. The RAS-RAF signaling pathway plays a key role in cellular differentiation and proliferation and is frequently associated with tumorigenesis. Specifically, we identified differentially expressed genes in BRAF mutant vs. wild-type cell lines, genes associated with high and low RAF copy number alteration cell lines, genes correlating in expression to growth inhibition by RAF-targeting compounds, and genes that either rescue or sensitize cell lines to BRAF knockdown by RNA interference. We further considered these genes within the overall context of physical interactions between their protein products. Highlighting the significant, research potential of our approach, our RAF-focused analysis identified both well-known and novel genes, supported by different lines of evidence, that mediate RAS-RAF signaling across multiple tissues. Positive control genes include members of the classical pathway, such as MAPK1, MAP2K1, and PI3K. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C70.