Abstract 2179: Computational pharmacogenomics analysis of human cancer cell lines

Abstract

Abstract Purpose: The goal of this study is to use cell-based drug screening and genome-wide molecular information to identify fundamental genomic alterations useful for clinical applications. Experimental Approach: Molecular data has been collected in the form of high-throughput microarray-based assays measuring gene expression and copy number changes for 294 cell lines, as well as cell-based drug sensitivity measures for 110 drugs. A computational analysis approach is taken to integrate information from the large cancer cell line datasets to discover predictive biomarkers that can be used to better guide targeted cancer drugs. Cancer genes and gene networks that are vital in a cancer cell's sensitivity or resistance to these drugs are identified by first locating genomic regions of recurrent amplification and deletion across the entire cell line panel. These regions are further analyzed for copy number associations with marked drug sensitivity or resistance. Those regions with copy number differences between drug sensitive and resistant cell lines are then examined on the gene expression level for cancer gene deregulation. Results: 156 chromosomal regions of recurrent copy number alteration are identified across the cell line panel. 15 compounds are associated with differential copy number between sensitive and resistant cell lines in one or more of these regions for a total of 77 significant drug-region associations. Out of these 77 associations, 13 of the regions also include genes which are differentially expressed between the sensitive and resistant cell lines. Conclusions: Genes that are deleted in drug sensitive or drug resistant cell lines can act as biomarkers for drug sensitivity or resistance respectively. Similarly, genes amplified in drug sensitive cell lines can act as biomarkers for drug sensitivity. Genes amplified in drug resistant cell lines provide hypotheses for combination therapy, as we believe that the amplification that is seen only in the drug resistant cell lines is a driving factor causing the resistance to that drug. Using the drug along with pharmacological inhibition or experimental knockdown of the gene commonly amplified in the resistant cell lines is hypothesized to alter the cell lines from a drug resistant to a drug sensitive state. Novel combination therapies for use in given drug resistant cell lines harboring specific amplifications are currently being validated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2179.