Abstract 956: Role of the cell cycle regulator LZTS1 in docetaxel resistance of prostate cancer cells and overcoming the docetaxel resistance by cell cycle pharmacological inhibitors.

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 and a signature of 99 highly differentially expressed genes (with Fold Change >5) potentially implicated in chemoresistance was generated. Results: We focused on the role of the cell cycle regulator LZTS1, which was strongly under-expressed in all the docetaxel-resistant cell lines. This underexpression was due to a stretch of 20 highly methylated CpGs in the region encompassing the exon 1 of the LZTS1 promoter in resistant cells. Knockdown of LZTS1 in IGR-CaP1 parental cells with siRNA showed that LZTS1 plays an important role in the acquisition of the resistant phenotype. Importantly, immunohistochemical staining showed a loss of LZTS1 expression in 33% of diagnostic biopsies obtained from patients with metastatic CRPC. Furthermore, we observed that targeting Cdc25C, a partner of LZTS1, with the Cdc25 pharmacological inhibitor NSC 663284 killed specifically the docetaxel-resistant cells. There are currently no CDC25C inhibitors tested in clinical trials, therefore we are currently investigating the role of other kinases that are involved in the G2/M checkpoint and in the regulation of CDC25C. Importantly, inhibitors of these kinases are currently being assessed in clinical trials. We wish to determine if targeting CDC25C and/or other kinases could kill docetaxel-resistant cells and if the use of such inhibitors could be a promising strategy to overcome docetaxel resistance in prostate cancer. Conclusion: High-density microarray genomic 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. Our findings identify an important role of LZTS1 in docetaxel resistance in prostate cancer through its regulation of CDC25C. It could also provide the framework for formulation of novel combined therapies that may improve taxane therapy efficacy or prevent chemoresistance in men with prostate cancer. Citation Format: Sophie Cotteret, Nader Al Nakouzi, Catherine Gaudin, Frederic Commo, Shanna Rajpar, Sandra Lejuste, Nicolas Martin, Karim Fizazi, Anne Chauchereau. Role of the cell cycle regulator LZTS1 in docetaxel resistance of prostate cancer cells and overcoming the docetaxel resistance by cell cycle pharmacological inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 956. doi:10.1158/1538-7445.AM2013-956