The next-generation antiandrogen drugs, XTANDI (enzalutamide), ZYTIGA (abiraterone acetate), ERLEADA (apalutamide) and NUBEQA (darolutamide) extend survival times and improve quality of life in patients with advanced prostate cancer. Despite these advances, resistance occurs frequently and there is currently no definitive cure for castration-resistant prostate cancer. 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 resensitize cells to apalutamide and darolutamide treatment. Furthermore, targeting AKR1C3 resensitizes 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 androgen receptor–targeted therapies in advanced prostate cancer.

中文翻译：

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下一代抗雄激素药物通过 AKR1C3/AR-V7 轴在晚期前列腺癌中的交叉耐药性

下一代抗雄激素药物XTANDI（恩杂鲁胺）、ZYTIGA（醋酸阿比特龙）、ERLEADA（阿帕鲁胺）和NUBEQA（darolutamide）可延长晚期前列腺癌患者的生存时间并改善生活质量。尽管取得了这些进展，但耐药性经常发生，目前还没有针对去势抵抗性前列腺癌的明确治愈方法。我们之前的研究发现，在治疗后会出现类似的对恩杂鲁胺或阿比特龙的耐药机制，并且这些疗法在晚期前列腺癌中存在交叉耐药性。在这里，我们显示耐恩杂鲁胺和阿比特龙的前列腺癌细胞对阿帕鲁胺和达洛鲁胺具有进一步的交叉耐药性。从机制上讲，我们已经确定 AKR1C3/AR-V7 轴赋予了这种交叉阻力。在 enzalutamide 耐药细胞中敲除 AR-V7 使细胞对 apalutamide 和 darolutamide 治疗重新敏感。此外，靶向 AKR1C3 通过抑制 AR-V7 使耐药细胞对 apalutamide 和 darolutamide 治疗重新敏感。C4-2B 细胞中的慢性 apalutamide 治疗可激活类固醇激素生物合成途径并增加 AKR1C3 表达，从而赋予对 enzalutamide、abiraterone 和 darolutamide 的抗性。总之，我们的结果表明，阿帕鲁胺和达洛鲁胺与恩杂鲁胺和阿比特龙具有相似的耐药机制。AKR1C3/AR-V7 复合物对晚期前列腺癌的第二代雄激素受体靶向治疗具有交叉耐药性。靶向 AKR1C3 通过抑制 AR-V7 使耐药细胞对 apalutamide 和 darolutamide 治疗重新敏感。C4-2B 细胞中的慢性 apalutamide 治疗可激活类固醇激素生物合成途径并增加 AKR1C3 表达，从而赋予对 enzalutamide、abiraterone 和 darolutamide 的抗性。总之，我们的结果表明，阿帕鲁胺和达洛鲁胺与恩杂鲁胺和阿比特龙具有相似的耐药机制。AKR1C3/AR-V7 复合物对晚期前列腺癌的第二代雄激素受体靶向治疗具有交叉耐药性。靶向 AKR1C3 通过抑制 AR-V7 使耐药细胞对 apalutamide 和 darolutamide 治疗重新敏感。C4-2B 细胞中的慢性 apalutamide 治疗可激活类固醇激素生物合成途径并增加 AKR1C3 表达，从而赋予对 enzalutamide、abiraterone 和 darolutamide 的抗性。总之，我们的结果表明，阿帕鲁胺和达洛鲁胺与恩杂鲁胺和阿比特龙具有相似的耐药机制。AKR1C3/AR-V7 复合物对晚期前列腺癌的第二代雄激素受体靶向治疗具有交叉耐药性。我们的研究结果表明，阿帕鲁胺和达洛鲁胺与恩杂鲁胺和阿比特龙具有相似的耐药机制。AKR1C3/AR-V7 复合物对晚期前列腺癌的第二代雄激素受体靶向治疗具有交叉耐药性。我们的研究结果表明，阿帕鲁胺和达洛鲁胺与恩杂鲁胺和阿比特龙具有相似的耐药机制。AKR1C3/AR-V7 复合物对晚期前列腺癌的第二代雄激素受体靶向治疗具有交叉耐药性。