Back

Brief Correspondence

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

By: Robert J. van Soest a lowast , Ellen S. de Morrée a , Charlotte F. Kweldam b , Corrina M.A. de Ridder a , Erik A.C. Wiemer c , Ron H.J. Mathijssen c , Ronald de Wit c and Wytske M. van Weerden a

European Urology, Volume 67 Issue 6, June 2015, Pages 981-985

Published online: 01 June 2015

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

Abstract Full Text Full Text PDF (2,5 MB) Patient Summary

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.

Patient summary

We found reduced efficacy of docetaxel, but not cabazitaxel, in enzalutamide-resistant prostate cancer.

Take Home Message

The androgen receptor (AR) confers in vivo cross-resistance between enzalutamide and docetaxel, but not cabazitaxel, in castration-resistant prostate cancer. Cabazitaxel remained highly effective in enzalutamide-resistant tumors, demonstrating greater antiproliferative properties independent of the AR pathway.

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

Footnotes

a Department of Urology, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

b Department of Pathology, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

c Department of Medical Oncology, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

lowast Corresponding author. Department of Urology, Erasmus University Medical Center, Dr. Molewaterplein 50, Be-331, 3015 GE Rotterdam, The Netherlands. Tel. +31-107043381; Fax: +31-107044661.

Place a comment

Your comment *

max length: 5000