Resistance invariably develops to anti-androgen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here we report that the transcriptional co-activator 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 research. 2017 Aug 17 [Epub ahead of print]
Lingyan Jin, Jesse Garcia, Emily Chan, Cecile de la Cruz, Ehud Segal, Mark Merchant, Samir Kharbanda, Ryan Raisner, Peter M Haverty, Zora Modrusan, Justin Ly, Edna Choo, Susan Kaufman, Maureen H Beresini, F Anthony Romero, Steven Magnuson, Karen E Gascoigne
Discovery Oncology, Genentech., Translational Oncology, Genentech., Department of Translational Oncology, Genentech., Calico Labs., Bioinformatics & Computational Biology, Genentech., Molecular Biology, Genentech Inc., Drug Metabolism and Pharmacokinetics, Genentech, Inc., Drug Metabolism and Pharmacokinetics, Genentech Inc., Biochemical and Cellular Pharmacology, Genentech., Chemistry, Unity Biotechnology., Discovery Oncology, Genentech .