Abstract 3586: Reactive oxygen species and antioxidant pathway in resistance to doxorubicin and paclitaxel in cancer
Authors: Ibrahim-zada Irada , Eng Lawson , Parissenti Amadeo , Pritchard Kathleen I. , Ozcelik Hilmi 
Published: February 2011

Abstract
Introduction: Resistance to anthracyclines and taxanes are the most challenging issue in breast cancer treatment. Genetic variations account for the observed inefficacy of the chemotherapy in breast cancer patients.
Aim: In this study we aimed to reveal novel genetic targets associated with anthracyclines’ and taxanes’ resistance in breast cancer patients.
Materials and methods: We used 125K Affymetrix SNP chip in NCI60 cell line panel treated with the drug of interests to perform genome-wide analysis (GWA) of the polymorphisms associated with resistance to doxorubicin and paclitaxel. Fine mapping of the identified candidate SNPs has been based on Genome Build 36.3. In vitro mRNA expression of the genes in doxorubicin- and paclitaxel resistant cell lines (MCF-7cc, A2780, and MES-SA) have been assessed by quantitative real-time PCR (ABI Prism 7500) and compared by t-test. The biological interactome was constructed on Ingenuity software to recreate the unique interacting pathway within candidate genes implicated in the resistance to both drugs.
Results: Using statistical approach previously published by our group, we defined sensitive and resistant cell lines both to doxorubicin and paclitaxel. GWA analyses identified 11 and 48 SNPs associated with doxorubicin and paclitaxel resistance, respectively, after statistical post-hoc adjustment by FDR-BH. Only 16 SNPs were mapped within the well-characterized genes (Doxorubicin: DSG1, FRMD6, RORA, and paclitaxel: ROBO1, SGCD, SNTG1, CCDC26, DCT, BTBD12, ZNF607, GRIK1, CFTR, PLHN2, PTPRD, SLC2A9 and KIAA0427). The mRNA expression analysis showed over-expression of the RORA and DSG1 genes, and under-expression of FRMD6, SGCD, and DCT in resistant cells. Interestingly, three doxorubicin- and six paclitaxel- associated genes were involved in the apoptotic process. ROBO1 is a direct target of p53 gene, whereas DSG1 is directly cleaved by CASP3, the major apoptotic executors. Two genes are participating in the defense mechanism against chemically induced oxidative stress, namely, RORA (as a direct ROS scavenger) and GRIK1 through β-catenin. The constructed interactome showed that there is cross-talk between genes associated with resistance to doxorubicin (directly) and paclitaxel (indirectly, via β-catenin and p53) within oxidative stress and anti-oxidant defense pathway.
Conclusion: Genome-wide analysis revealed that genetic variations within apoptotic pathways are correlated with resistance to anthracyclines and paclitaxel. Doxorubicin and paclitaxel share common intracellular targets that define resistance to treatment. Oxidative stress and anti-oxidant defense pathways might serve as pharmacogenomic targets and potential predictive markers for resistance to anthracyclines and taxanes.
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 3586.