Resistance to taxane chemotherapy is frequently observed in metastatic prostate cancer. The androgen receptor (AR) is a major driver of prostate cancer and a key regulator of the G1-S cell cycle checkpoint, promoting cancer cell proliferation by irreversible passage to the S-phase. We hypothesized that AR signaling inhibitor (ARSi) darolutamide in combination with docetaxel could augment antitumor effect by impeding the proliferation of taxane-resistant cancer cells. We monitored cell viability in organoids, tumor volume and PSA secretion in patient-derived xenografts (PDXs) and analyzed cell cycle and signaling pathway alterations. Combination treatment increased anti-tumor effect in androgen-sensitive, AR-positive prostate cancer organoids and PDXs. Equally beneficial effects of darolutamide added to docetaxel were observed in a castration-resistant model, progressive on docetaxel, enzalutamide and cabazitaxel. In vitro studies showed that docetaxel treatment with simultaneous darolutamide resulted in a reduction of cells entering the S-phase in contrast to only docetaxel. Molecular analysis in the prostate cancer cell line LNCaP revealed an upregulation of Cyclin Dependent Kinase inhibitor p21, supporting blockade of S-phase entry and cell proliferation. Our results provide a preclinical support for combining taxanes and darolutamide as a multimodal treatment strategy in metastatic prostate cancer patients progressive on ARSi and taxane chemotherapy.

中文翻译：

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多西紫杉醇中添加 Darolutamide 通过 G1-S 期细胞周期阻滞增强前列腺癌模型的抗肿瘤作用

在转移性前列腺癌中经常观察到对紫杉烷化疗的耐药性。雄激素受体 (AR) 是前列腺癌的主要驱动因素，也是 G1-S 细胞周期检查点的关键调节因子，通过不可逆地进入 S 期促进癌细胞增殖。我们假设 AR 信号抑制剂 (ARSi) 达洛鲁胺与多西紫杉醇联合使用可以通过阻止紫杉烷耐药癌细胞的增殖来增强抗肿瘤作用。我们监测了类器官中的细胞活力、肿瘤体积和患者来源的异种移植物 (PDX) 中的 PSA 分泌，并分析了细胞周期和信号通路的变化。联合治疗可增强雄激素敏感、AR 阳性前列腺癌类器官和 PDX 的抗肿瘤作用。在去势抵抗模型中观察到将达洛鲁胺添加到多西他赛中的同样有益的效果，在多西他赛、恩杂鲁胺和卡巴他赛上渐进。体外研究表明，与仅用多西紫杉醇治疗相比，多西紫杉醇同时联合达洛鲁胺治疗可导致进入 S 期的细胞减少。前列腺癌细胞系 LNCaP 的分子分析揭示了细胞周期蛋白依赖性激酶抑制剂 p21 的上调，支持阻止 S 期进入和细胞增殖。我们的研究结果为联合紫杉烷类药物和达洛鲁胺作为一种多模式治疗策略，用于治疗经 ARSi 和紫杉烷类化疗进展的转移性前列腺癌患者提供了临床前支持。