Abstract
Abstract BACKGROUND Platinum analogues and taxanes are clinically effective in esophagogastric (EG) cancers and demonstrate significant non-cross resistance. Nevertheless, resistance (primary or acquired) remains a major therapeutic problem. We have developed platinum and docetaxel resistant cell line models and aim to use gene expression profiling for hypothesis generation to identify; predictive biomarkers; novel mechanisms of action and resistance; therapeutic targets and to provide insight into mechanisms of cross resistance. This will inform optimal cytotoxic and targeted therapy combination strategies. METHODS Resistant daughter cell lines were generated from 3 parental EG cancer cell lines (OE33, OE21, AGS) by exposure to increasing concentrations of oxaliplatin, cisplatin and docetaxel for at least 12 months. Cell viability was measured at 72h by the MTT assay. IC50 values were calculated in Prism Software and P<0.05 were statistically significant (Student's t-test). Affymetrix GeneChip Exon 1.0 were used to measure gene expression. Gene expression data were normalized in GeneSpring GX v10.0.1 using RMA for summarisation and baseline transformation of log transformed data to the median. The microarrays passed QC analysis, including hybridisation and labelling controls, Pos_vs_Neg_AUC and all probe Set RLE mean. RESULTS Initial data available compared daughter oxaliplatin resistant OE21ox4 line to OE21wt. Of the 17881 core genes present on the array, 14727 were expressed above background (20th −100th percentile) and of these the expression of 528 transcripts was altered by ≥ 2 fold (3 fold, n=113 and 5 fold, n=26). MMP9 demonstrated the highest change (14.3 fold decrease in resistant cells). Interestingly, ABCC2/ MRP, known to confer resistance to many cytotoxics, including taxanes but not platinums, was reduced by 6.3 fold in resistant cells. Gene ontology analysis identified transcripts whose products are associated with the extracellular region as significantly represented in the 538 entity gene set (P=6.971 × 10−7). Seven biological pathways were significantly altered in oxaliplatin-resistant compared to the sensitive parental OE21 cells (2fold geneset, n=528): alpha VI beta IV integrin (P=0.004), EGFR1 (P=0.003), ID (P=2.41^-4), IL1 (P=0.013), IL2 (P=0.027), IL6 (P=0.021), TCR (P=0.039). The αVIβIV and IL1 pathways were also significantly altered after chemotherapy in a parallel study of serial biopsies from EG cancer patients in our group. CONCLUSION We have a panel of EG cancer cell lines representative of clinical subgroups of the disease and have developed resistant daughter lines to oxaliplatin, cisplatin and docetaxel. A preliminary analysis of the OE21 oesophageal squamous carcinoma cell line and its oxaliplatin resistant daughter line is presented. A comparative gene expression data analysis of the entire panel of cell lines will be presented at the meeting. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 2570.
Published Version
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