Prostate cancer is a frequent malignancy in older men and has a very high 5-year survival rate if diagnosed early. The prognosis is much less promising if the tumor has already spread outside the prostate gland. Targeted treatments mainly aim at blocking androgen receptor (AR) signaling and initially show good efficacy. However, tumor progression due to AR-dependent and AR-independent mechanisms is often observed after some time, and novel treatment strategies are urgently needed. Dysregulation of the PI3K/AKT/mTOR pathway in advanced prostate cancer and its implication in treatment resistance has been reported. We compared the impact of PI3K/AKT/mTOR pathway inhibitors with different selectivity profiles on in vitro cell proliferation and on caspase 3/7 activation as a marker for apoptosis induction, and observed the strongest effects in the androgen-sensitive prostate cancer cell lines VCaP and LNCaP. Combination treatment with the AR inhibitor darolutamide led to enhanced apoptosis in these cell lines, the effects being most pronounced upon cotreatment with the pan-PI3K inhibitor copanlisib. A subsequent transcriptomic analysis performed in VCaP cells revealed that combining darolutamide with copanlisib impacted gene expression much more than individual treatment. A comprehensive reversal of the androgen response and the mTORC1 transcriptional programs as well as a marked induction of DNA damage was observed. Next, an in vivo efficacy study was performed using the androgen-sensitive patient-derived prostate cancer (PDX) model LuCaP 35 and a superior efficacy was observed after the combined treatment with copanlisib and darolutamide. Importantly, immunohistochemistry analysis of these treated tumors showed increased apoptosis, as revealed by elevated levels of cleaved caspase 3 and Bcl-2-binding component 3 (BBC3). In conclusion, these data demonstrate that concurrent blockade of the PI3K/AKT/mTOR and AR pathways has superior antitumor efficacy and induces apoptosis in androgen-sensitive prostate cancer cell lines and PDX models.

中文翻译：

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前列腺癌模型中雄激素受体和 PI3K/AKT/mTOR 通路的双重靶向可提高抗肿瘤功效并促进细胞凋亡

前列腺癌是老年男性常见的恶性肿瘤，如果及早诊断，五年生存率非常高。如果肿瘤已经扩散到前列腺之外，则预后就不太乐观。靶向治疗主要旨在阻断雄激素受体（AR）信号传导，并初步显示出良好的疗效。然而，一段时间后经常会观察到由于AR依赖性和AR非依赖性机制导致的肿瘤进展，因此迫切需要新的治疗策略。据报道，晚期前列腺癌中 PI3K/AKT/mTOR 通路的失调及其对治疗耐药的影响。我们比较了具有不同选择性特征的 PI3K/AKT/mTOR 通路抑制剂对体外细胞增殖和作为细胞凋亡诱导标志物的 caspase 3/7 激活的影响，并观察到在雄激素敏感的前列腺癌细胞系 VCaP 中效果最强和 LNCaP。与 AR 抑制剂 darolutamide 联合治疗导致这些细胞系细胞凋亡增强，与泛 PI3K 抑制剂 copanlisib 联合治疗时效果最为明显。随后在 VCaP 细胞中进行的转录组分析表明，将 darolutamide 与 copanlisib 联合使用对基因表达的影响远大于单独治疗。观察到雄激素反应和 mTORC1 转录程序的全面逆转以及 DNA 损伤的显着诱导。接下来，使用雄激素敏感的人源性前列腺癌（PDX）模型LuCaP 35进行体内疗效研究，在copanlisib和darolutamide联合治疗后观察到优异的疗效。重要的是，这些治疗肿瘤的免疫组织化学分析显示细胞凋亡增加，如裂解的 caspase 3 和 Bcl-2 结合成分 3 (BBC3) 水平升高所揭示的。总之，这些数据表明，同时阻断 PI3K/AKT/mTOR 和 AR 通路具有优异的抗肿瘤功效，并在雄激素敏感的前列腺癌细胞系和 PDX 模型中诱导细胞凋亡。