Graham Laura S, Su Lih-Jen, Nicklawsky Andrew, Feng Frances Xiuyan, Orlicky David, Petraccione Joseph, Salzmann-Sullivan Maren, Nordeen Steven K, Flaig Thomas W
Division of Medical Oncology, Department of Internal Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA.
Biostatistics and Bioinformatics, University of Colorado Cancer Center, Aurora, CO 80045, USA.
Cancers (Basel). 2025 Feb 10;17(4):593. doi: 10.3390/cancers17040593.
The use of supraphysiologic testosterone, particularly when alternated with an anti-androgen agent in men with metastatic castration-resistant prostate cancer (CRPC), has demonstrated promising results in clinical trials. As the use of this therapy in clinical practice is more widely adopted, there will be a growing need to understand the mechanisms of resistance. To that end, we independently derived three separate cell models of testosterone-sensitive CRPC. From each CRPC line, high dose testosterone-resistance (HTR) lines were selected. We demonstrated the differential response of the three CRPC lines to a high dose of testosterone in vitro and in vivo. We subsequently demonstrated the resistance of the HTR lines to testosterone and varying responses to testosterone withdrawal in vivo. The heterogeneity in responses to hormonal manipulation is correlated with varying levels of androgen receptor expression within the population. Overall, we show that we have developed three models of HTR that can be used to study the mechanisms of high dose testosterone resistance and identify potential therapeutic targets.
使用超生理剂量的睾酮，尤其是在转移性去势抵抗性前列腺癌（CRPC）男性患者中与抗雄激素药物交替使用时，已在临床试验中显示出有前景的结果。随着这种疗法在临床实践中的使用越来越广泛，对耐药机制的理解需求也将日益增加。为此，我们独立衍生出三种不同的睾酮敏感型CRPC细胞模型。从每个CRPC细胞系中，筛选出高剂量睾酮抗性（HTR）细胞系。我们证明了这三种CRPC细胞系在体外和体内对高剂量睾酮的不同反应。随后，我们证明了HTR细胞系对睾酮的抗性以及在体内对睾酮撤药的不同反应。对激素操纵反应的异质性与群体内雄激素受体表达水平的变化相关。总体而言，我们表明我们已经开发出三种HTR模型，可用于研究高剂量睾酮抗性的机制并确定潜在的治疗靶点。
