在化耐性前列腺癌中,雄激素受体活性的重编程是由截断的变体形成的
Mitchell G Lawrence1, Shivakumar Keerthikumar2, Scott L Townley3
1Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia; Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; Cabrini Institute, Cabrini Health, Malvern, Australia; Melbourne Urological Research Alliance, Monash University, Clayton, Australia.
European urology focus
|April 12, 2025
概括
像ARv567es这样的雄激素受体 (AR) 变体通过改变基因表达来驱动前列腺癌治疗耐药性. 识别ARv567es可能有助于指导治疗抗性前列腺癌的治疗决策.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 遗传学 遗传学 是一个
背景情况:
- 前列腺癌细胞在治疗压力下发展出构成性活跃的雄激素受体 (AR) 变体.
- 由于与全长AR的共表达,AR变体在治疗耐药性中的作用受到争论.
研究的目的:
- 研究AR变异如何影响AR染色质占用率和治疗反应.
- 为了区分AR变体在存在和缺乏全长AR的影响.
主要方法:
- 利用患者衍生的转移性前列腺癌与多种AR变化的异种移植.
- 采用染色体免疫沉和RNA测序来分析AR结合和转录基因特征.
- 在小鼠模型中评估治疗对割和双极性雄激素治疗的反应.
主要成果:
- 鉴定出一个独特的瘤群体,其特征是ARv567es表达,这是AR基因重排的结果.
- 阳性ARv567es瘤表现出独特的表观基因组和转录特征,包括改变的AR调节和AR抑制基因.
- 这些瘤表现出对割和双极雄激素治疗的耐药性,在共同表达全长AR时抑制了转录反应和破坏了AR自调节.
结论:
- 通过基因重新排列,ARv567es的出现会诱导转录重编程,并在前列腺癌中产生治疗耐药性.
- ARv567es作为一种潜在的生物标志物,用于指导晚期前列腺癌的治疗策略.
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