1. Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer.
- Author
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Jin L, Garcia J, Chan E, de la Cruz C, Segal E, Merchant M, Kharbanda S, Raisner R, Haverty PM, Modrusan Z, Ly J, Choo E, Kaufman S, Beresini MH, Romero FA, Magnuson S, and Gascoigne KE
- Subjects
- Animals, Cell Growth Processes drug effects, Cell Line, Tumor, E1A-Associated p300 Protein deficiency, E1A-Associated p300 Protein genetics, E1A-Associated p300 Protein metabolism, Female, Gene Expression, Gene Knockdown Techniques, Humans, Male, Mice, Mice, SCID, Molecular Targeted 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, Transfection, Xenograft Model Antitumor Assays, E1A-Associated p300 Protein antagonists & inhibitors, Prostatic Neoplasms, Castration-Resistant drug therapy, Small Molecule Libraries pharmacology
- Abstract
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 in vitro and in vivo 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. Cancer Res; 77(20); 5564-75. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2017
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