Abstract 823: Integration of microRNA and gene expression signatures from several models of Docetaxel-resistant prostate cancer cell lines

Abstract

Abstract Background: Docetaxel is the standard treatment for metastatic castration-resistant prostate cancer (CRPC) since 2004 and overall survival benefit in CRPC has been demonstrated in docetaxel-treated patients. In spite of this benefit, a drug resistance is eventually observed in all patients, leaving few therapeutic options. Therefore, it is crucial to identify predictive markers that enable selection of patients who will respond to treatment. Methods: Three docetaxel-resistant prostate cancer cell lines (LNCaP, PC3 and IGR-CaP1) were obtained by continuous exposure to Docetaxel. A high-density genomic profiling by cDNA microarrays (Agilent technologies) was performed to compare sensitive and chemoresistant cell lines. The differential expression levels of 377 microRNAs between resistant and sensitive parental cell lines were measured by Taqman Low Density Array (TLDA, Applied Biosystems technology). Each determination was generated from biological replicates in the absence of drug. Results: A gene expression signature of 583 genes was generated by the bootstrap method (Fold change>2 for each doses of Docetaxel, P value <10-5) in IGR-CaP1 cells. Based on the hypothesis of a biological effect due to increasing drug, a second microarray expression profile was identified using a 5-parameters logistic regression model. This analysis led to the identification of 486 genes associated with resistance to increasing doses of docetaxel (with a P value ≤ 10-5 and a fold change between the first and the last dose of drug ≤ 2). 45 genes were common in the two analyses. A 65 miRs expression profile of docetaxel resistance was determined in all three cell lines using two reference miRs. Interestingly, we identified the under-expression of three clusters of miRs in the resistant cells. In particular, the under-expression of the miR 141-200c cluster was inversely correlated to the over-expression of its target genes Jagged1 (JAG1) and dll1(DLL1), which were identified in the gene expression signature. JAG1 and DLL1 are ligands for Notch receptors, thus we are currently exploring the role of the miR-200c/ZEB1/JAG1 axis and the Notch signalling pathway in mechanisms of Docetaxel resistance. Conclusion: High-density microarray genomic and microRNA profiling analyses comparing chemo-resistant versus sensitive prostate cancer cell lines were used to identify signatures of genes and microRNAs, and signaling pathways potentially implicated in Docetaxel resistance. Ultimately, integration of data from gene and microRNA expression will allow the identification of biomarkers to select patients that could benefit from Docetaxel chemotherapy. It could also provide the framework for formulation of novel therapies that may improve taxane therapy efficacy in men with prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 823. doi:1538-7445.AM2012-823