Wüstmann Neele, Seifert Konstantin Egon, Humberg Verena, Vieler Julia, Grundmann Norbert, Steinestel Julie, Tiedje Dorothee, Duensing Stefan, Krabbe Laura-Maria, Bögemann Martin, Schrader Andres Jan, Bernemann Christof, Schlack Katrin
Department of Urology, University Hospital Muenster, Albert-Schweitzer Campus 1 A1, 48149, Muenster, Germany.
Institute for Bioinformatics, University Hospital Muenster, Muenster, Germany.
Biomark Res. 2023 Apr 5;11(1):37. doi: 10.1186/s40364-023-00481-w.
Androgen receptor (AR) splice variants (AR-Vs) have been discussed as a biomarker in prostate cancer (PC). However, some reports question the predictive property of AR-Vs. From a mechanistic perspective, the connection between AR full length (AR-FL) and AR-Vs is not fully understood. Here, we aimed to investigate the dependence of AR-FL and AR-V expression levels on AR gene activity. Additionally, we intended to comprehensively analyze presence of AR-FL and three clinically relevant AR-Vs (AR-V3, AR-V7 and AR-V9) in different stages of disease, especially with respect to clinical utility in PC patients undergoing AR targeted agent (ARTA) treatment.
AR-FL and AR-V levels were analyzed in PC and non-PC cell lines upon artificial increase of AR pre-mRNA using either drug treatment or AR gene activation. Furthermore, expression of AR-FL and AR-Vs was determined in PC specimen at distinct stages of disease (primary (n = 10) and metastatic tissues (n = 20), liquid biopsy samples (n = 422), mCRPC liquid biopsy samples of n = 96 patients starting novel treatment). Finally, baseline AR-FL and AR-V status was correlated with clinical outcome in a defined cohort of n = 65 mCRPC patients undergoing ARTA treatment.
We revealed rising levels of AR-FL accompanied with appearance and increase of AR-Vs in dependence of elevated AR pre-mRNA levels. We also noticed increase in AR-FL and AR-V levels throughout disease progression. AR-V expression was always associated with high AR-FL levels without any sample being solely AR-V positive. In patients undergoing ARTA treatment, AR-FL did show prognostic, yet not predictive validity. Additionally, we observed a substantial clinical response to ARTA treatment even in AR-V positive patients. Accordingly, multivariate analysis did not demonstrate independent significance of AR-Vs in neither predictive nor prognostic clinical utility.
We demonstrate a correlation between AR-FL and AR-V expression during PC progression; with AR-V expression being a side-effect of elevated AR pre-mRNA levels. Clinically, AR-V positivity relies on high levels of AR-FL, making cells still vulnerable to ARTA treatment, as demonstrated by AR-FL and AR-V positive patients responding to ARTA treatment. Thus, AR-FL and AR-V might be considered as a prognostic, yet not predictive biomarker in mCRPC patients.
雄激素受体（AR）剪接变体（AR-Vs）已被讨论作为前列腺癌（PC）的一种生物标志物。然而，一些报告对AR-Vs的预测特性提出质疑。从机制角度来看，AR全长（AR-FL）与AR-Vs之间的联系尚未完全明确。在此，我们旨在研究AR-FL和AR-V表达水平对AR基因活性的依赖性。此外，我们打算全面分析不同疾病阶段AR-FL和三种临床相关AR-Vs（AR-V3、AR-V7和AR-V9）的存在情况，特别是关于接受AR靶向药物（ARTA）治疗的PC患者的临床效用。
在使用药物治疗或AR基因激活人工增加AR前体mRNA后，分析PC和非PC细胞系中的AR-FL和AR-V水平。此外，在疾病不同阶段（原发性（n = 10）和转移性组织（n = 20）、液体活检样本（n = 422）、开始新治疗的n = 96例患者的mCRPC液体活检样本）的PC标本中测定AR-FL和AR-Vs的表达。最后，在一个由n = 65例接受ARTA治疗的mCRPC患者组成的特定队列中，将基线AR-FL和AR-V状态与临床结果相关联。
我们发现随着AR前体mRNA水平升高，AR-FL水平上升，同时伴有AR-Vs的出现和增加。我们还注意到在整个疾病进展过程中AR-FL和AR-V水平升高。AR-V表达始终与高AR-FL水平相关，没有任何样本仅为AR-V阳性。在接受ARTA治疗的患者中，AR-FL确实显示出预后价值，但没有预测有效性。此外，我们观察到即使在AR-V阳性患者中，对ARTA治疗也有显著的临床反应。因此，多变量分析未显示AR-Vs在预测或预后临床效用方面具有独立意义。
我们证明了PC进展过程中AR-FL与AR-V表达之间的相关性；AR-V表达是AR前体mRNA水平升高的副作用。临床上，AR-V阳性依赖于高AR-FL水平，这使得细胞仍然易受ARTA治疗影响，正如AR-FL和AR-V阳性患者对ARTA治疗有反应所证明的那样。因此，在mCRPC患者中，AR-FL和AR-V可被视为一种预后生物标志物，但不是预测性生物标志物。
