Androgen Receptor Splice Variant 7 Drives the Growth of Castration Resistant Prostate Cancer without Being Involved in the Efficacy of Taxane Chemotherapy

Abstract

Expression of androgen receptor (AR) splice variant 7 (AR-V7) has been identified as the mechanism associated with the development of castration-resistant prostate cancer (CRPC). However, a potential link between AR-V7 expression and resistance to taxanes, such as docetaxel or cabazitaxel, has not been unequivocally demonstrated. To address this, we used LNCaP95-DR cells, which express AR-V7 and exhibit resistance to enzalutamide and docetaxel. Interestingly, LNCaP95-DR cells showed cross-resistance to cabazitaxel. Furthermore, these cells had increased levels of P-glycoprotein (P-gp) and their sensitivity to both docetaxel and cabazitaxel was restored through treatment with tariquidar, a P-gp antagonist. Results generated demonstrated that P-gp mediated cross-resistance between docetaxel and cabazitaxel. Although the LNCaP95-DR cells had increased expression of AR-V7 and its target genes (UBE2C, CDC20), the knockdown of AR-V7 did not restore sensitivity to docetaxel or cabazitaxel. However, despite resistance to docetaxel and carbazitaxel, EPI-002, an antagonist of the AR amino-terminal domain (NTD), had an inhibitory effect on the proliferation of LNCaP95-DR cells, which was similar to that achieved with the parental LNCaP95 cells. On the other hand, enzalutamide had no effect on the proliferation of either cell line. In conclusion, our results suggested that EPI-002 may be an option for the treatment of AR-V7-driven CRPC, which is resistant to taxanes.

Docetaxel/cabazitaxel and fatty acid binding protein 5 inhibitors produce synergistic inhibition of prostate cancer growth

“…21,22 Similar to docetaxel, cabazitaxel produced dose-dependent cytotoxicity in each cell-line tested: PC3 cells with an IC 50 value of 1.6 nM ( Figure 5A); DU-145 cells with an IC 50 value of 0.2 nM ( Figure 5B); and 22Rv1 cells with an IC 50 value of 0.3 nM ( Figure 5C); similar to previously published literature. 32,33 Combination of cabazitaxel with SBFI-102 or SBFI-103 resulted in greater cytotoxicity in all three cell-lines than each drug when administered alone ( Figure 6). CI values were calculated across a range of cabazitaxel concentrations, and synergistic relationships between cabazitaxel and the FABP5 inhibitors were observed (Table 2).…”

“…Cabazitaxel (Figure D) is a second‐line chemotherapeutic for advanced metastatic PCa, and is often utilized after tumors begin to develop docetaxel‐resistance . Similar to docetaxel, cabazitaxel produced dose‐dependent cytotoxicity in each cell‐line tested: PC3 cells with an IC 50 value of 1.6 nM (Figure A); DU‐145 cells with an IC 50 value of 0.2 nM (Figure B); and 22Rv1 cells with an IC 50 value of 0.3 nM (Figure C); similar to previously published literature . Combination of cabazitaxel with SBFI‐102 or SBFI‐103 resulted in greater cytotoxicity in all three cell‐lines than each drug when administered alone (Figure ).…”

Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: the OCUU-CRPC study

“…In the present study, the outcomes of CRPC were significantly superior in the enzalutamide than the flutamide group, in terms of the PSA response. However, owing to the challenges in treating enzalutamide-and taxane-resistant CRPC, other therapeutic strategies need to be established and validated before enzalutamide initiation [21].…”

Loss of Fibroblast-Dependent Androgen Receptor Activation in Prostate Cancer Cells is Involved in the Mechanism of Acquired Resistance to Castration

“…In human PCa cell lines, expression of AR-V7 mediates resistance to a new generation of AR-targeted therapies, such as enzalutamide and abiraterone [53]. In addition, Shimizu et al recently reported that knockdown of AR-V7 in LNCaP95-DR cells did not restore sensitivity to docetaxel and cabazitaxel, suggesting that AR-V7 may be not involved in taxane resistance [54]. Thus, expression of AR-V7 has been proposed for the assessment of suitability for taxane chemotherapy [55].…”