Docetaxel-based chemotherapy is established as a first-line treatment and standard of care for patients with metastatic castration-resistant prostate cancer. However, half of the patients do not respond to treatment and those do respond eventually become refractory.
A better understanding of the resistance mechanisms to taxane chemotherapy is both urgent and clinical significant, as taxanes (docetaxel and cabazitaxel) are being used in various clinical settings. Sustained signaling through the androgen receptor (AR) has been established as a hallmark of CRPC. Recently, splicing variants of AR (AR-Vs) that lack the ligand-binding domain (LBD) have been identified. These variants are constitutively active and drive prostate cancer growth in a castration-resistant manner. In taxane-resistant cell lines, we found the expression of a major variant, AR-V7, was upregulated. Furthermore, ectopic expression of two clinically relevant AR-Vs (AR-V7 and ARV567es), but not the full-length AR (AR-FL), reduced the sensitivities to taxanes in LNCaP cells.
Treatment with taxanes inhibited the transcriptional activity of AR-FL, but not those of AR-Vs. This could be explained, at least in part, due to the inability of taxanes to block the nuclear translocation of AR-Vs. Through a series of deletion constructs, the microtubule-binding activity was mapped to the LBD of AR. Finally, taxane-induced cytoplasm sequestration of AR-FL was alleviated when AR-Vs were present.
These findings provide evidence that constitutively active AR-Vs maintain the AR signaling axis by evading the inhibitory effects of microtubule-targeting agents, suggesting that these AR-Vs play a role in resistance to taxane chemotherapy.
Oncotarget. 2015 Jun 22. [Epub ahead of print]
Zhang G1,2,3, Liu X2,3, Li J1,2,3, Ledet E4,5,3, Alvarez X6, Qi Y7,3, Fu X1, Sartor O4,5,3, Dong Y1,7,3, Zhang H2,3.
1 College of Life Sciences, Jilin University, Changchun, P.R. China.
2 Department of Pathology, Tulane University School of Medicine, New Orleans, Louisiana, USA.
3 Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana, USA.
4 Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.
5 Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana, USA.
6 Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, USA.
7 Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana, USA.