Abstract 2599: Taxane pharmacogenomics: Identifying genetic variation associated with drug cytotoxicity using a genome-wide association approach and a cell line model system

Background Taxane, a class of common anticancer agent, is widely used to treat many cancers. Among the taxanes, paclitaxel and docetaxel are the most commonly used agents. The mechanism of action for taxane drugs is through stabilizing microtubules by enhancing tubulin assembly and against depolymerization, thereby disrupting the dynamics of the microtubule. Large inter-individual variation has been observed in response to taxane treatment. Therefore, in the present study, we conducted a genome-wide association (GWA) study to identify genetic polymorphisms that might contribute to variation in response to taxanes drugs using the “Human Variation Panel” lymphoblastoid cell line (LCL) model system that consists of 287 ethnically defined cell lines. Method Genome-wide SNP and basal gene expression data were obtained for 287 LCLs using Illumina HumanHap 550K, 510S BeadChips, Affymetix SNP Array 6.0 and Affymetrix U133 plus 2.0 GeneChip. Cytotoxicity assay was also performed in the same cell lines for both paclitaxel and docetaxel. Candidate genes were selected based on an integrated analysis of genome-wide SNPs, expression array data and IC50 values (a cytotoxicity phenotype indicating the drug concentration required for 50% inhibition of maximal cell growth) for paclitaxel and docetaxel. SiRNA screening was performed to functionally validate those top candidates, followed by MTS assay in a breast cancer cell line, MDA-MB231. Results Of the 54,000 probe sets considered, 390 probe sets, representing 272 unique annotated genes, were found to be associated with docetaxel cytotoxicity (IC50 value) with p value 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 2599.