Abstract 3948: Identification of a new therapeutic target in prostate cancer from siRNA screening in Docetaxel-resistant cells

Abstract

Abstract Background: Prostate cancer is the most common male cancer and the second leading cause of death. Docetaxel is a chemotherapy used to manage the Metastatic Castrate-Resistant Prostate Cancer (mCRPC). Inexorably, patients will develop resistance to this treatment. Therefore, new efforts are needed to understand the molecular mechanisms of resistance, enabling the discovery of specific therapeutic targets to avoid this resistance in patients. Methods: We developed a series of Docetaxel-resistant cell lines (IGR-CaP1-R, PC3-R, 22RV1-R, LNCaP-R) and we generated a signature of 1,006 highly differentially expressed genes potentially implicated in chemoresistance. Moreover, we performed a high throughput siRNA screening in IGR-CaP1, allowing us to select 60 genes with a functional role in Docetaxel resistance. Results: We focused our attention on the role of a chaperone protein, which is localized in the endoplasmic reticulum and belongs to the FKBP-type peptidyl-prolyl cis/trans isomerase (PPIase) family. This protein is highly overexpressed in Docetaxel-resistant prostate cancer cell lines and its overexpression is specifically induced by agents targeting microtubules such as taxanes (Docetaxel, Cabazitaxel, and Paclitaxel) or Nocodazole. Induction of its expression was also observed in tumors obtained from sub-cutaneous injection of IGR-CaP1 after Docetaxel treatment in vivo. Specific inhibition with siRNA leads to cell death of the Docetaxel-resistant IGR-CaP1-R and PC3-R cell lines as well as the Cabazitaxel-resistant IGR-CaP1 cells. In LNCaP-R and 22RV1-R resistant cell lines, it decreases the proliferation rate. Moreover, knockdown of this protein restores Docetaxel response of all the resistant cell lines. In addition, although this chaperone is highly expressed in several non cancerous cells, its extinction does not affect cell growth suggesting a different function of the protein between chemoresistant cells and non cancerous cells. Preliminary observations suggest that this protein could be mislocalized in Docetaxel-resistant cells in some cytoplasmic vesicles, as a consequence of taxane treatment. Conclusion: We identified a new chaperone harbouring an enzymatic activity which could be a relevant therapeutic target in chemoresistant CRPC. We are now focusing on the identification of a specific inhibitor in order to validate the role of this target in two Docetaxel-resistant prostate cancer mice models established within the laboratory. Citation Format: Marine Garrido, Nicolas J-p Martin, Catherine Gaudin, Elaine Del Nery, Jacques Camonis, Franck Perez, Stéphanie Lerondel, Alain Le Pape, Karim Fizazi, Anne Chauchereau. Identification of a new therapeutic target in prostate cancer from siRNA screening in Docetaxel-resistant cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3948. doi:10.1158/1538-7445.AM2015-3948