Co-targeting BET, CBP, and p300 inhibits neuroendocrine signalling in androgen receptor-null prostate cancer

IF 5.6 2区医学 Q1 ONCOLOGY

The Journal of Pathology Pub Date : 2024-04-05 DOI:10.1002/path.6280

Nicholas Choo, Shivakumar Keerthikumar, Susanne Ramm, Daisaku Ashikari, Linda Teng, Birunthi Niranjan, Shelley Hedwards, Laura H Porter, David L Goode, Kaylene J Simpson, Renea A Taylor, Gail P Risbridger, Mitchell G Lawrence

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Abstract

There are diverse phenotypes of castration-resistant prostate cancer, including neuroendocrine disease, that vary in their sensitivity to drug treatment. The efficacy of BET and CBP/p300 inhibitors in prostate cancer is attributed, at least in part, to their ability to decrease androgen receptor (AR) signalling. However, the activity of BET and CBP/p300 inhibitors in prostate cancers that lack the AR is unclear. In this study, we showed that BRD4, CBP, and p300 were co-expressed in AR-positive and AR-null prostate cancer. A combined inhibitor of these three proteins, NEO2734, reduced the growth of both AR-positive and AR-null organoids, as measured by changes in viability, size, and composition. NEO2734 treatment caused consistent transcriptional downregulation of cell cycle pathways. In neuroendocrine models, NEO2734 treatment reduced ASCL1 levels and other neuroendocrine markers, and reduced tumour growth in vivo. Collectively, these results show that epigenome-targeted inhibitors cause decreased growth and phenotype-dependent disruption of lineage regulators in neuroendocrine prostate cancer, warranting further development of compounds with this activity in the clinic. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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联合靶向 BET、CBP 和 p300 可抑制雄激素受体无效前列腺癌的神经内分泌信号传导

前列腺癌（包括神经内分泌疾病）有多种表型，它们对药物治疗的敏感性也各不相同。BET 和 CBP/p300 抑制剂对前列腺癌的疗效至少部分归因于它们能够减少雄激素受体（AR）信号传导。然而，BET和CBP/p300抑制剂在缺乏AR的前列腺癌中的活性尚不清楚。在这项研究中，我们发现 BRD4、CBP 和 p300 在 AR 阳性和 AR 缺失的前列腺癌中共同表达。这三种蛋白的联合抑制剂NEO2734可减少AR阳性和AR无效器官组织的生长，具体表现为存活率、大小和组成的变化。NEO2734 处理会导致细胞周期通路的转录下调。在神经内分泌模型中，NEO2734 治疗降低了 ASCL1 水平和其他神经内分泌标志物，并减少了体内肿瘤的生长。总之，这些结果表明，表观基因组靶向抑制剂会导致神经内分泌性前列腺癌的生长减慢和表型依赖性系谱调节因子的破坏，因此有必要在临床上进一步开发具有这种活性的化合物。© 2024 作者。病理学杂志》由 John Wiley & Sons Ltd 代表大不列颠及爱尔兰病理学会出版。

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来源期刊

The Journal of Pathology 医学-病理学

CiteScore

14.10

自引率

1.40%

发文量

144

审稿时长

3-8 weeks

期刊介绍： The Journal of Pathology aims to serve as a translational bridge between basic biomedical science and clinical medicine with particular emphasis on, but not restricted to, tissue based studies. The main interests of the Journal lie in publishing studies that further our understanding the pathophysiological and pathogenetic mechanisms of human disease. The Journal of Pathology welcomes investigative studies on human tissues, in vitro and in vivo experimental studies, and investigations based on animal models with a clear relevance to human disease, including transgenic systems. As well as original research papers, the Journal seeks to provide rapid publication in a variety of other formats, including editorials, review articles, commentaries and perspectives and other features, both contributed and solicited.