Background:: The androgen receptor (AR) pathway is a key driver of neoplastic behaviour in the different stages of metastatic prostate cancer (mPCa). Targeting the AR therefore remains the cornerstone for mPCa treatment. We have previously reported that activation of AR signalling affects taxane chemo-sensitivity in preclinical models of castration resistant PCa (CRPC). Here, we explored the anti-tumour efficacy of the AR targeted inhibitor enzalutamide combined with cabazitaxel. Methods:: We used the AR positive CRPC model PC346C-DCC-K to assess the in vitro and in vivo activity of combining enzalutamide with cabazitaxel. Subsequent validation studies were performed using an enzalutamide resistant VCaP model. To investigate the impact of AR signalling on cabazitaxel activity we used quantitative live-cell imaging of tubulin stabilization and apoptosis related nuclear fragmentation. Findings:: Enzalutamide strongly amplified cabazitaxel anti-tumour activity in the patient-derived xenograft models PC346C-DCC-K (median time to humane endpoint 77 versus 48 days, P<0.0001) and VCaP-Enza-B (median time to humane endpoint 80 versus 53 days, P<0.001). Although enzalutamide treatment by itself was ineffective in reducing tumour growth, it significantly suppressed AR signalling in PC346C-DCC-K tumours as shown by AR target gene expression. The addition of enzalutamide enhanced cabazitaxel induced apoptosis as shown by live-cell imaging (P<0.001). Interpretation:: Our study demonstrates that cabazitaxel efficacy can be improved by simultaneous blocking of AR signalling by enzalutamide, even if AR targeted treatment no longer affects tumour growth. These findings support clinical studies that combine AR targeted inhibitors with cabazitaxel in CRPC.
|Publication status||Published - 1 Nov 2021|
Bibliographical noteFunding Information:
The authors would like to thank Andrea Sacchetti for providing support in flow cytometry. This study was financially supported by an unrestricted grant by Sanofi, however Sanofi was not involved in the design and interpretation of this study.
The authors would like to thank Andrea Sacchetti for providing support in flow cytometry. This study was financially supported by an unrestricted grant by Sanofi, however Sanofi was not involved in the design and interpretation of this study. This study was supported by Sanofi. The PC346C-DCC-K and VCaP-Enza-B cell lines will be made available to academic institutions under the Erasmus MC Biological Uniform Material Transfer Agreement. The RNA-sequencing data of enzalutamide treated PC346C-DCC-K tumours will be made available through GEO (accession number GSE185587).
© 2021 The Authors