Department of Urology, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Department of Urology, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Eur Urol. 2015 Jun;67(6):981-985. doi: 10.1016/j.eururo.2014.11.033. Epub 2014 Dec 4.
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.
We found reduced efficacy of docetaxel, but not cabazitaxel, in enzalutamide-resistant prostate cancer.
转移性去势抵抗性前列腺癌（CRPC）的治疗选择随着新型雄激素受体（AR）靶向药物阿比特龙和恩扎鲁胺在化疗前的既定疗效而发展。然而，人们对紫杉烷类药物多西他赛和卡巴他赛与这些 AR 靶向药物之间的交叉耐药性产生了担忧，并且最佳药物治疗顺序尚不清楚。我们研究了多西他赛和卡巴他赛在恩扎鲁胺耐药性 CRPC 中的体内疗效，以及这些药物之间交叉耐药的机制。患有恩扎鲁胺耐药肿瘤和恩扎鲁胺-naïve 肿瘤的去势小鼠接受了多西他赛和卡巴他赛治疗。分析了肿瘤生长动力学、AR 核定位、AR 调节基因表达、Ki67 表达以及前列腺特异性抗原、多西他赛和卡巴他赛的血清水平。多西他赛抑制了恩扎鲁胺-naïve 肿瘤的肿瘤生长、AR 核定位和 AR 调节基因表达，但在恩扎鲁胺耐药肿瘤中无效，表现出体内交叉耐药性。相比之下，卡巴他赛在恩扎鲁胺耐药肿瘤中仍然非常有效，并且与 AR 通路无关，显示出比多西他赛更好的抗肿瘤活性。这些发现表明，AR 通路能够在 CRPC 中赋予恩扎鲁胺和多西他赛之间的体内交叉耐药性，但不能赋予卡巴他赛。
我们发现多西他赛在恩扎鲁胺耐药性前列腺癌中的疗效降低，但卡巴他赛没有。
