Current treatments for castration resistant prostate cancer (CRPC) largely fall into two classes: androgen receptor (AR)-targeted therapies such as the next-generation antiandrogen therapies (NGAT), enzalutamide and abiraterone, and taxanes such as docetaxel and cabazitaxel. Despite improvements in outcomes, patients still succumb to the disease due to the development of resistance. Further complicating the situation is lack of a well-defined treatment sequence and potential for cross-resistance between therapies. We have developed several models representing CRPC with acquired therapeutic resistance. Here, we utilized these models to assess putative cross-resistance between treatments. We find that resistance to enzalutamide induces resistance to abiraterone and vice versa, but resistance to neither alters sensitivity to taxanes. Acquired resistance to docetaxel induces cross-resistance to cabazitaxel but not to enzalutamide or abiraterone. Correlating responses with known mechanisms of resistance indicates that AR variants are associated with resistance to NGATs, whereas the membrane efflux protein ABCB1 is associated with taxane resistance. Mechanistic studies show that AR variant-7 (AR-v7) is involved in NGAT resistance but not resistance to taxanes. Our findings suggest the existence of intra cross-resistance within a drug class (i.e., within NGATs or within taxanes), whereas inter cross-resistance between drug classes does not develop. Furthermore, our data suggest that resistance mechanisms differ between drug classes. These results may have clinical implications by showing that treatments of one class can be sequenced with those of another, but caution should be taken when sequencing similar classed drugs. In addition, the development and use of biomarkers indicating resistance will improve patient stratification for treatment. Mol Cancer Ther; 17(10); 2197–205. ©2018 AACR.

中文翻译：

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内部与内部交叉耐药性决定晚期前列腺癌紫杉烷和 AR 靶向治疗之间的治疗顺序

目前对去势抵抗性前列腺癌 (CRPC) 的治疗主要分为两类：雄激素受体 (AR) 靶向疗法，例如下一代抗雄激素疗法 (NGAT)、恩杂鲁胺和阿比特龙，以及紫杉烷类药物，例如多西他赛和卡巴他赛。尽管结果有所改善，但由于耐药性的发展，患者仍然死于该疾病。使情况进一步复杂化的是缺乏明确定义的治疗顺序和治疗之间的交叉耐药性的可能性。我们开发了几种代表具有获得性治疗耐药性的 CRPC 的模型。在这里，我们利用这些模型来评估治疗之间假定的交叉耐药性。我们发现对恩杂鲁胺的耐药性会诱导对阿比特龙的耐药性，反之亦然，但对这两种药物的耐药性都不会改变对紫杉类的敏感性。获得性对多西他赛的耐药性会诱导对卡巴他赛的交叉耐药性，但不会对恩杂鲁胺或阿比特龙产生交叉耐药性。将反应与已知的耐药机制相关联表明，AR 变体与对 NGAT 的耐药性相关，而膜外排蛋白 ABCB1 与紫杉烷耐药相关。机理研究表明，AR 变体 7 (AR-v7) 与 NGAT 抗性有关，但与对紫杉烷类的抗性无关。我们的研究结果表明，药物类别内（即在 NGAT 内或紫杉烷内）存在内部交叉耐药性，而药物类别之间不发生交叉耐药性。此外，我们的数据表明，药物类别之间的耐药机制不同。这些结果可能通过表明一类治疗可以与另一类治疗进行排序而具有临床意义，但在对同类药物进行测序时应谨慎。此外，指示耐药性的生物标志物的开发和使用将改善患者的治疗分层。摩尔癌症治疗; 17(10); 2197-205。©2018 AACR。