Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 20; pp. 5564 - 5575
• Main Authors: Jin, Lingyan, Garcia, Jesse, Chan, Emily, de la Cruz, Cecile, Segal, Ehud, Merchant, Mark, Kharbanda, Samir, Raisner, Ryan, Haverty, Peter M, Modrusan, Zora, Ly, Justin, Choo, Edna, Kaufman, Susan, Beresini, Maureen H, Romero, F Anthony, Magnuson, Steven, Gascoigne, Karen E
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 15.10.2017
• Subjects: Acetylation; Androgen receptors; Androgens; Animals; Castration; Cell Growth Processes - drug effects; Cell Line, Tumor; E1A-Associated p300 Protein - antagonists & inhibitors; E1A-Associated p300 Protein - deficiency; E1A-Associated p300 Protein - genetics; E1A-Associated p300 Protein - metabolism; Event-related potentials; Female; Gene Expression; Gene Knockdown Techniques; Humans; Male; Medical treatment; Mice; Mice, SCID; Molecular Targeted Therapy; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Protein Domains; Random Allocation; Receptors, Androgen - metabolism; Signal Transduction - drug effects; Small Molecule Libraries - pharmacology; Therapeutic targets; Transcription; Transfection; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-17-0314

Resistance invariably develops to antiandrogen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, we report that the transcriptional coactivator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth and Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptional activity of the androgen receptor and its target gene expression. Our findings offer a preclinical proof of concept for small-molecule therapies to target the CBP/p300 bromodomain as a strategy to treat castration-resistant prostate cancer. .