Abstract 1716: Mechanisms of resistance in carboplatin, docetaxel and dual drug resistant ovarian cancer cell lines

Abstract

Abstract Carboplatin and docetaxel are two standard chemotherapeutics used to treat ovarian cancer. Patients often exhibit resistance to single agent therapy, and dual agent therapy was developed to overcome this resistance. However, resistance still commonly occurs in dual agent therapy. It is known that specific changes in gene expression occur in single agent resistance, but it is not known whether resistance to combined chemotherapy involves novel gene expression changes or if resistance is only the sum of changes seen in single agent resistant cells. Using the chemotherapy-naïve A2780 ovarian cancer cell line, we have generated three resistant cell lines including carboplatin and docetaxel single agent resistant lines (A2780CBN, and A2780DXL respectively), and a carboplatin/docetaxel dual resistant line (A2780CBNDXL) by exposing A2780 cells to increasing concentrations of drug until a dose is reached where resistance could no longer be developed. The concentration of drug at which 50% of cells die (IC50) was measured for reach resistant cell line using a clonogenic assay. The IC50 of A2780CBN is 8×10−5 M, 13-fold more resistant than the parent line. The IC50 of A2780DXL is 3×10−7 M, 5000-fold more resistant than the parent line. The IC50 of A2780CBNDXL is 8×10−6 M for carboplatin and 8×10−9 M for docetaxel. Changes in gene expression associated with the development of resistance in each cell line were identified by microarray analysis on Agilent 4×44k total human genome arrays. In the A2780CBN line there were a total of 1209 significant changes in gene expression, in the A2780DXL line there were 955 changes, and in the A2780CBNDXL line there were 1336 changes. The majority of changes in each cell line (70%) were unique, indicating that novel changes in gene expression occur in the dual line. A Functional Interaction Network-based analysis was conducted on the microarray data identify important gene clusters acting in the drug resistant A2780 ovarian cancer cell lines. Ten major clusters were found in the A2780CBN line, 8 clusters in the A2780DXL line and 10 clusters in the A2780CBNDXL line. Although similar clusters occurred among the lines, the genes in them were different and several unique clusters occurred in the dual line. Functional enrichment analysis will be done for every cluster and the most significant pathways will be taken into further consideration for validation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1716. doi:10.1158/1538-7445.AM2011-1716