Cross-Resistance Among Next-Generation Antiandrogen Drugs Through the AKR1C3/AR-V7 Axis in Advanced Prostate Cancer.
Cross-Resistance Among Next-Generation Antiandrogen Drugs Through the AKR1C3/AR-V7 Axis in Advanced Prostate Cancer.
复制标题
晚期前列腺癌中下一代抗雄激素药物通过AKR 1C 3/AR-V7轴的交叉耐药性。
DOI：
10.1158/1535-7163.mct-20-0015
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发表时间：
2020-08
影响因子：
5.7
通讯作者：
Liu C
中科院分区：
文献类型：
--
作者：
Zhao J;Ning S;Lou W;Yang JC;Armstrong CM;Lombard AP;D'Abronzo LS;Evans CP;Gao AC;Liu C
新一代抗雄激素药物XTANDI®(恩扎鲁胺)、ZYTIGA®(醋酸阿比拉通)、ERLEADA™(阿帕鲁胺)和NUBEQA(达鲁他胺)可延长晚期前列腺癌患者的生存时间并改善其生活质量。尽管有这些进展，耐药性仍然经常发生，目前还没有明确的治疗去势抵抗前列腺癌(CRPC)的方法。我们以前的研究发现，在晚期前列腺癌治疗后，对苯扎鲁胺或阿比特龙产生类似的耐药机制，并且这些疗法之间存在交叉耐药。在这里，我们显示对苯扎鲁胺和阿比特龙耐药的前列腺癌细胞对阿帕鲁胺和达鲁他胺有进一步的交叉耐药。从机制上讲，我们已经确定AKR1C3/AR-V7轴赋予了这种交叉阻力。敲除苯扎鲁胺耐药细胞中的AR-V7使细胞对阿帕鲁胺和达鲁他胺治疗重新敏感。此外，靶向AKR1C3通过抑制AR-V7使耐药细胞对阿帕鲁胺和达鲁他胺治疗重新敏感。慢性阿帕鲁胺治疗C4-2B细胞激活类固醇激素生物合成途径，增加AKR1C3的表达，从而使其对苯扎鲁胺、阿比特龙和达鲁他胺产生耐药性。综上所述，我们的结果提示阿帕鲁胺和达鲁他胺与苯扎鲁胺和阿比特龙具有相似的耐药机制。AKR1C3/AR-V7复合体对晚期前列腺癌的第二代AR靶向治疗具有交叉耐药性。
The next generation anti-androgen drugs, XTANDI® (Enzalutamide), ZYTIGA® (Abiraterone acetate), ERLEADA™ (Apalutamide) and NUBEQA (Darolutamide) extend survival times and improve quality of life in advanced prostate cancer patients. Despite these advances, resistance occurs frequently and there is currently no definitive cure for Castration-Resistant Prostate Cancer (CRPC). Our previous studies identified that similar mechanisms of resistance to enzalutamide or abiraterone occur following treatment and cross-resistance exists between these therapies in advanced prostate cancer. Here we show that enzalutamide and abiraterone resistant prostate cancer cells are further cross-resistant to apalutamide and darolutamide. Mechanistically, we have determined that the AKR1C3/AR-V7 axis confers this cross-resistance. Knockdown of AR-V7 in enzalutamide resistant cells re-sensitize cells to apalutamide and darolutamide treatment. Furthermore, targeting AKR1C3 re-sensitizes resistant cells to apalutamide and darolutamide treatment through AR-V7 inhibition. Chronic apalutamide treatment in C4-2B cells activates the steroid hormone biosynthesis pathway and increases AKR1C3 expression which confers resistance to enzalutamide, abiraterone and darolutamide. In conclusion, our results suggest that apalutamide and darolutamide share similar resistant mechanisms with enzalutamide and abiraterone. The AKR1C3/AR-V7 complex confers cross-resistance to second generation AR-targeted therapies in advanced prostate cancer.