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

被引：116

作者：

Jin, Lingyan ^{[1
]}

Garcia, Jesse ^{[2
]}

Chan, Emily ^{[2
]}

de la Cruz, Cecile ^{[2
]}

Segal, Ehud ^{[2
]}

Merchant, Mark ^{[2
]}

Kharbanda, Samir ^{[3
]}

Raisner, Ryan ^{[1
]}

Haverty, Peter M. ^{[4
]}

Modrusan, Zora ^{[5
]}

Ly, Justin ^{[6
]}

Choo, Edna ^{[6
]}

Kaufman, Susan ^{[7
]}

Beresini, Maureen H. ^{[7
]}

Romero, F. Anthony ^{[8
]}

Magnuson, Steven ^{[9
]}

Gascoigne, Karen E. ^{[1
]}

机构：

[1] Genentech Inc, Dept Discovery Oncol, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Translat Oncol, San Francisco, CA 94080 USA

[3] Calico Labs, San Francisco, CA USA

[4] Genentech Inc, Dept Bioinformat, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA

[6] Genentech Inc, Dept DMPK, San Francisco, CA 94080 USA

[7] Genentech Inc, Dept Biochem & Cellular Pharmacol, San Francisco, CA 94080 USA

[8] Unity Biotechnol, Brisbane, CA USA

[9] Genentech Inc, Dept Discovery Chem, San Francisco, CA 94080 USA

来源：

CANCER RESEARCH | 2017年 / 77卷 / 20期

关键词：

ANDROGEN-RECEPTOR GENE; XENOGRAFT MODELS; BINDING PROTEIN; P300; EXPRESSION; ABIRATERONE; PROGRESSION; INHIBITION; SURVIVAL; MUTATION;

D O I：

10.1158/0008-5472.CAN-17-0314

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Resistance invariably develops to antiandrogen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, wereport 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. (C) 2017 AACR.

引用

页码：5564 / 5575

页数：12

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