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Patients with metastatic castration resistant prostate cancer (mCRPC) frequently develop therapeutic resistance to taxane chemotherapy and antiandrogens. Cabazitaxel (CBZ) is a second-line taxane chemotherapeutic agent that provides additional survival benefits to patients with advanced disease. In this study we sought to identify the mechanism of action of combined CBZ and androgen receptor (AR) targeting, in pre-clinical models of advanced prostate cancer. We found tha CBZ induced mitotic spindle collapse and multi-nucleation by targeting the microtubule de-polymerizing kinesins and inhibiting AR. In androgen responsive tumors, treatment with the AR inhibitor, Enzalutamide, overcame resistance to CBZ. Combination treatment of human CRPC xenografts with CBZ and Enzalutamide reversed epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial-transition (MET) and led to multi-nucleation, while retaining nuclear AR. In a transgenic mouse model of androgen-responsive prostate cancer, CBZ treatment induced MET, glandular re-differentiation and AR nuclear localization that was inhibited by androgen deprivation. Collectively, our pre-clinical studies demonstrate that prostate tumor resistance to Cabazitaxel can be overcome by antiandrogen-mediated EMT-MET cycling in androgen-sensitive tumors, but not in CRPC. Moreover, AR splice variants may preclude patients with advanced disease from responding to Cabazitaxel chemotherapy and antiandrogen combination therapy. This evidence enables a significant insight into therapeutic cross-resistance to taxane chemotherapy and androgen-deprivation therapy in advanced prostate cancer.

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<div>Abstract<p>Patients with metastatic castration-resistant prostate cancer (CRPC) frequently develop therapeutic resistance to taxane chemotherapy and antiandrogens. Cabazitaxel is a second-line taxane chemotherapeutic agent that provides additional survival benefits to patients with advanced disease. In this study, we sought to identify the mechanism of action of combined cabazitaxel and androgen receptor (AR) targeting in preclinical models of advanced prostate cancer. We found that cabazitaxel induced mitotic spindle collapse and multinucleation by targeting the microtubule depolymerizing kinesins and inhibiting AR. In androgen-responsive tumors, treatment with the AR inhibitor, enzalutamide, overcame resistance to cabazitaxel. Combination treatment of human CRPC xenografts with cabazitaxel and enzalutamide reversed epithelial–mesenchymal transition (EMT) to mesenchymal–epithelial transition (MET) and led to multinucleation, while retaining nuclear AR. In a transgenic mouse model of androgen-responsive prostate cancer, cabazitaxel treatment induced MET, glandular redifferentiation, and AR nuclear localization that was inhibited by androgen deprivation. Collectively, our preclinical studies demonstrate that prostate tumor resistance to cabazitaxel can be overcome by antiandrogen-mediated EMT-MET cycling in androgen-sensitive tumors but not in CRPC. Moreover, AR splice variants may preclude patients with advanced disease from responding to cabazitaxel chemotherapy and antiandrogen combination therapy. This evidence enables a significant insight into therapeutic cross-resistance to taxane chemotherapy and androgen deprivation therapy in advanced prostate cancer. <i>Cancer Res; 76(4); 912–26. ©2015 AACR</i>.</p></div>

<p>Supplemental Figures 1-7. Supplemental Figure 1: This figure shows the results of the dose response of human prostate cancer lines to antiandrogen (Enzalutamide) and Docetaxel (1st line taxane chemotherapy) as single agents and in combination treatment. It also describes the effect of AR variants on prostate cancer cell migration. Supplemental Figure 2: This figures describes the findings on the combined effect of Cabazitaxel ( 2nd line taxane chemotherapy) and Enzalutamie (antiandrogen) on AR expression, cellular localization and transcriptional activity ( target gene expression) in androgen-sensitive prostate cancer cells, VCaP. Supplemental Figure 3: This figure shows the results from confocal microscopy analysis on the cellular localization of AR variants, tubulin expression and nuclear presence in Cabazitaxel-resistant prostate cancer cells. Supplemental Figure 4: This Figure indicates the effect of Cabazitaxel treatment on kinesin protein and mRNA expression in androgen-responsive prostate cancer cells VCaP. Supplemental Figure 5: This Figure shows the results from immunofluorescence for detection of centrosomal amplification (pericentrin) in CRPC 22Rv1 cells after Cabazitaxel and antiandrogen treatment. Supplemental Figure 6: This Figure schematically summarizes the therapeutic regimen/dosing for in vivo treatment of pre-clinical transgenic model of prostate cancer with Cabazitaxel and antiandrogens and the consequences of treatment on body weight. Supplementary Figure 7: This Figure schematically describes the therapeutic dosing regimen of Cabazitaxel treatment in prostate cancer human xenograft model (22Rv1 castration resistant prostate cancer) in vivo. It also provides information on the antitumor effect of treatment on tumor growth and body weight of mice.</p>