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

Choo, N; Keerthikumar, S; Ramm, S; Ashikari, D; Teng, L; Niranjan, B; Hedwards, S; Porter, LH; Goode, DL; Simpson, KJ; Taylor, RA; Risbridger, GP; Lawrence, MG

Author(s): Choo, N; Keerthikumar, S; Ramm, S; Ashikari, D; Teng, L; Niranjan, B; Hedwards, S; Porter, LH; Goode, DL; Simpson, KJ; Taylor, RA; Risbridger, GP; Lawrence, MG;
Details: Publication Year 2024-06,Volume 263,Issue #2,Page 242-256
Journal Title: Journal of Pathology
Publication Type: Research article
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.
Publisher: Wiley
Keywords: Male; Humans; *Receptors, Androgen/metabolism/genetics; *Signal Transduction; Animals; *E1A-Associated p300 Protein/metabolism/genetics; Transcription Factors/metabolism/genetics; Cell Line, Tumor; Cell Proliferation/drug effects; Cell Cycle Proteins/metabolism/genetics; Prostatic Neoplasms, Castration-Resistant/pathology/metabolism/drug; therapy/genetics; Prostatic Neoplasms/pathology/metabolism/drug therapy/genetics; Gene Expression Regulation, Neoplastic; Mice; Xenograft Model Antitumor Assays; Bromodomain Containing Proteins; CREB-Binding Protein; Brd4; CBP/p300; Neo2734; Pdx; neuroendocrine; organoids; prostate cancer
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1002/path.6280
Open Access at Publisher's Site: https://doi.org/10.1002/path.6280
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-07-04 12:35:20

Last Modified: 2024-07-04 12:38:43