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      Targeting the Androgen Receptor Confers In Vivo Cross-resistance Between Enzalutamide and Docetaxel, But Not Cabazitaxel, in Castration-resistant Prostate Cancer.

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          Abstract

          Treatment options for metastatic castration-resistant prostate cancer (CRPC) have evolved with the established benefit of the novel androgen receptor (AR)-targeted agents abiraterone and enzalutamide in the prechemotherapy setting. However, concerns regarding cross-resistance between the taxanes docetaxel and cabazitaxel and these AR-targeted agents have arisen, and the optimal drug treatment sequence is unknown. We investigated the in vivo efficacy of docetaxel and cabazitaxel in enzalutamide-resistant CRPC, and mechanisms of cross-resistance between these agents. Castrated mice harboring enzalutamide-resistant tumors and enzalutamide-naïve tumors were treated with docetaxel and cabazitaxel. Tumor growth kinetics, AR nuclear localization, AR-regulated gene expression, Ki67 expression, and serum levels of prostate-specific antigen, docetaxel, and cabazitaxel were analyzed. Docetaxel inhibited tumor growth, AR nuclear localization, and AR-regulated gene expression in enzalutamide-naïve tumors, but did not in enzalutamide-resistant tumors, demonstrating in vivo cross-resistance. By contrast, cabazitaxel remained highly effective in enzalutamide-resistant tumors and demonstrated superior antitumor activity compared to docetaxel, independent of the AR pathway. These findings demonstrate that the AR pathway is able to confer in vivo cross-resistance between enzalutamide and docetaxel, but not cabazitaxel, in CRPC.

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          Author and article information

          Journal
          Eur. Urol.
          European urology
          1873-7560
          0302-2838
          Jun 2015
          : 67
          : 6
          Affiliations
          [1 ] Department of Urology, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. Electronic address: r.vansoest@erasmusmc.nl.
          [2 ] Department of Urology, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
          [3 ] Department of Pathology, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
          [4 ] Department of Medical Oncology, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
          Article
          S0302-2838(14)01216-0
          10.1016/j.eururo.2014.11.033
          25484141
          62fc53a9-e8dc-4bea-b02c-b20a1aa671ac
          Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
          History

          Androgen receptor,Cabazitaxel,Castration-resistant prostate cancer,Cross-resistance,Docetaxel,Enzalutamide,Taxanes

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