Intra versus Inter Cross-resistance Determines Treatment Sequence between Taxane and AR-Targeting Therapies in Advanced Prostate Cancer
Intra versus Inter Cross-resistance Determines Treatment Sequence between Taxane and AR-Targeting Therapies in Advanced Prostate Cancer
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DOI：
10.1158/1535-7163.mct-17-1269
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发表时间：
2018-10-01
影响因子：
5.7
通讯作者：
Gao, Allen C.
中科院分区：
文献类型：
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作者：
Lombard, Alan P.;Liu, Liangren;Gao, Allen C.
目前对去势耐受前列腺癌(CRPC)的治疗主要分为两类：雄激素受体(AR)靶向治疗，如下一代抗雄激素治疗(NGAT)、苯扎鲁胺和阿比特龙，以及紫杉烷类药物，如多西紫杉醇和卡巴紫杉醇。尽管结果有所改善，但由于耐药性的发展，患者仍然屈从于这种疾病。使情况更加复杂的是，缺乏明确的治疗顺序和治疗之间交叉耐药的可能性。我们已经开发了几个代表获得性治疗耐药的CRPC的模型。在这里，我们利用这些模型来评估治疗之间可能的交叉耐药。我们发现，对苯扎鲁胺的耐药性导致对阿比特龙的耐药性，反之亦然，但对两者的耐药性都不会改变对紫杉烷的敏感性。对多西紫杉醇的获得性耐药导致对卡巴紫杉醇的交叉耐药，但不会对苯扎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变异与对NGATS的耐药有关，而膜外排蛋白ABCB1与紫杉烷耐药有关。机制研究表明，AR变异体7(AR-v7)参与了对Ngat的抗性，但与紫杉烷类药物的抗性无关。我们的发现表明，药物类别内(即，在NGAT或紫杉烷类内)存在内部交叉耐药，而药物类别之间不会产生交叉耐药。此外，我们的数据表明，不同药物类别的耐药机制不同。这些结果可能具有临床意义，因为这些结果表明，一类治疗可以与另一类治疗进行排序，但在对类似分类的药物进行排序时应谨慎。此外，指示耐药性的生物标记物的开发和使用将改善患者的治疗分层。(C)2018年AACR。
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. (C) 2018 AACR.