Taxanes are important drugs in the treatment of ovarian cancers, but their efficacy is limited by intrinsic and acquired drug resistance. Over-expression of the MDR1 gene and its product, P-glycoprotein, is a well-characterized resistance mechanism to taxanes, but non-MDR1 taxane resistance mechanisms are not well elucidated. To study the mechanisms of non-MDR1 multidrug resistance related to taxanes, we established multiple MDR1-negative and MDR1-positive taxane resistant variants from four ovarian cancer cell lines (A2780/1A9, ES-2, MES-OV and OVCAR-3) by continuous exposure of the cells to either paclitaxel or docetaxel with or without the P-glycoprotein inhibitor PSC-833 (Valspodar). We profiled gene expression and gene copy number alterations in these cell lines using cDNA microarrays, and identified a transcriptomic signature that predicts in vitro non-MDR1 resistance, a portion of which was imprinted by gene dosage changes. Functional network analyses for genes associated with the taxane resistance signature revealed two highly significant networks built around FN1 and CDKN1A which are associated with cell adhesion, cell-to-cell signaling and cell cycle regulation. We also identified epithelial-mesenchymal transition (EMT) marker genes which are significantly associated with non-MDR1 resistance. Migration potential in wound-scratch-assay was markedly enhanced in non-MDR1 resistant variants compared to parental cells. Our results suggest that ECM-interacting genes, EMT-like changes and cell cycle regulatory elements may play important roles in resistance to 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 1526.