Miller Katie Joanna, Henry Isla, Maylin Zoe, Smith Christopher, Arunachalam Einthavy, Pandha Hardev, Asim Mohammad
Department of Clinical & Experimental Medicine, University of Surrey, Guildford, United Kingdom.
Front Oncol. 2023 Mar 1;13:1129140. doi: 10.3389/fonc.2023.1129140. eCollection 2023.
Persistent androgen receptor (AR) signalling is the main driver of prostate cancer (PCa). Truncated isoforms of the AR called androgen receptor variants (AR-Vs) lacking the ligand binding domain often emerge during treatment resistance against AR pathway inhibitors such as Enzalutamide. This review discusses how AR-Vs drive a more aggressive form of PCa through the regulation of some of their target genes involved in oncogenic pathways, enabling disease progression. There is a pressing need for the development of a new generation of AR inhibitors which can repress the activity of both the full-length AR and AR-Vs, for which the knowledge of differentially expressed target genes will allow evaluation of inhibition efficacy. This review provides a detailed account of the most common variant, AR-V7, the AR-V7 regulated genes which have been experimentally validated, endeavours to understand their relevance in aggressive AR-V driven PCa and discusses the utility of the downstream protein products as potential drug targets for PCa treatment.
持续性雄激素受体(AR)信号传导是前列腺癌(PCa)的主要驱动因素。在对恩杂鲁胺等AR通路抑制剂产生耐药性的过程中,常出现缺乏配体结合域的AR截短异构体,称为雄激素受体变体(AR-Vs)。本综述讨论了AR-Vs如何通过调控其一些参与致癌途径的靶基因来驱动更具侵袭性的PCa形式,从而促使疾病进展。迫切需要开发新一代AR抑制剂,其能够抑制全长AR和AR-Vs的活性,了解差异表达的靶基因将有助于评估抑制效果。本综述详细介绍了最常见的变体AR-V7、已通过实验验证的AR-V7调控基因,努力理解它们在由AR-V驱动的侵袭性PCa中的相关性,并讨论了下游蛋白质产物作为PCa治疗潜在药物靶点的效用。