Tolkach Yuri, Kremer Anika, Lotz Gábor, Schmid Matthias, Mayr Thomas, Förster Sarah, Garbe Stephan, Hosni Sana, Cronauer Marcus V, Kocsmár Ildikó, Kocsmár Éva, Riesz Péter, Alajati Abdullah, Ritter Manuel, Ellinger Jörg, Ohlmann Carsten-Henning, Kristiansen Glen
Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany.
Institute of Pathology, University Hospital Cologne, 50937 Cologne, Germany.
Cancers (Basel). 2022 Sep 13;14(18):4441. doi: 10.3390/cancers14184441.
Canonical androgen receptor (AR) signaling regulates a network of DNA repair genes in prostate cancer (PCA). Experimental and clinical evidence indicates that androgen deprivation not only suppresses DNA repair activity but is often synthetically lethal in combination with PARP inhibition. The present study aimed to elucidate the impact of AR splice variants (AR-Vs), occurring in advanced or late-stage PCA, on DNA repair machinery.
Two hundred and seventy-three tissue samples were analyzed, including primary hormone-naïve PCA, primary metastases, hormone-sensitive PCA on androgen deprivation therapy (ADT) and castration refractory PCA (CRPC group). The transcript levels of the target genes were profiled using the nCounter platform. Experimental support for the findings was gained in AR/AR-V7-expressing LNCaP cells subjected to ionizing radiation.
AR-Vs were present in half of hormone-sensitive PCAs on androgen deprivation therapy (ADT) and two-thirds of CRPC samples. The presence of AR-Vs is highly correlated with increased activity in the AR pathway and DNA repair gene expression. In AR-V-expressing CRPC, the DNA repair score increased by 2.5-fold as compared to AR-V-negative samples. Enhanced DNA repair and the deregulation of DNA repair genes by AR-V7 supported the clinical data in a cell line model.
The expression of AR splice variants such as AR-V7 in PCA patients following ADT might be a reason for reduced or absent therapy effects in patients on additional PARP inhibition due to the modulation of DNA repair gene expression. Consequently, AR-Vs should be further studied as predictive biomarkers for therapy response in this setting.
经典雄激素受体（AR）信号传导调节前列腺癌（PCA）中的DNA修复基因网络。实验和临床证据表明，雄激素剥夺不仅会抑制DNA修复活性，而且与PARP抑制联合使用时往往具有合成致死性。本研究旨在阐明晚期PCA中出现的AR剪接变体（AR-Vs）对DNA修复机制的影响。
分析了273个组织样本，包括原发性未接受激素治疗的PCA、原发性转移灶、接受雄激素剥夺治疗（ADT）的激素敏感性PCA和去势抵抗性PCA（CRPC组）。使用nCounter平台分析靶基因的转录水平。在接受电离辐射的AR/AR-V7表达的LNCaP细胞中获得了对这些发现的实验支持。
AR-Vs存在于一半接受雄激素剥夺治疗（ADT）的激素敏感性PCA和三分之二的CRPC样本中。AR-Vs的存在与AR途径活性增加和DNA修复基因表达高度相关。在表达AR-V的CRPC中，与AR-V阴性样本相比，DNA修复评分增加了2.5倍。AR-V7增强的DNA修复和DNA修复基因的失调在细胞系模型中支持了临床数据。
ADT后PCA患者中AR-V7等AR剪接变体的表达可能是由于DNA修复基因表达的调节，导致接受额外PARP抑制的患者治疗效果降低或无效的原因。因此，在这种情况下，AR-Vs应作为治疗反应的预测生物标志物进行进一步研究。
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