Targeting the P300/CBP Axis in Lethal Prostate Cancer

Overview

Journal Cancer Discov

Specialty Oncology

Date 2021 Jan 12

PMID 33431496

Citations 94

Authors

Jonathan Welti

Adam Sharp

Nigel Brooks

Wei Yuan

Christopher McNair

Saswati N Chand

Abhijit Pal

Ines Figueiredo

Ruth Riisnaes

Bora Gurel

Jan Rekowski

Denisa Bogdan

William West

Barbara Young

Meera Raja

Amy Prosser

Jordan Lane

Stuart Thomson

Jenny Worthington

Stuart Onions

Jonathan Shannon

Silvia Paoletta

Richard Brown

Don Smyth

Gareth W Harbottle

Veronica S Gil

Susana Miranda

Mateus Crespo

Ana Ferreira

Rita Pereira

Nina Tunariu

Suzanne Carreira

Antje J Neeb

Jian Ning

Amanda Swain

David Taddei

Matthew J Schiewer

Karen E Knudsen

Neil Pegg

Johann S de Bono

Affiliations

Soon will be listed here.

Abstract

Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of AR (AR-SV). Inhibitors of transcriptional coactivators that regulate AR activity, including the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal prostate cancer. Herein, we validate targeting p300/CBP as a therapeutic strategy for lethal prostate cancer and describe CCS1477, a novel small-molecule inhibitor of the p300/CBP conserved bromodomain. We show that CCS1477 inhibits cell proliferation in prostate cancer cell lines and decreases AR- and C-MYC-regulated gene expression. In AR-SV-driven models, CCS1477 has antitumor activity, regulating AR and C-MYC signaling. Early clinical studies suggest that CCS1477 modulates KLK3 blood levels and regulates CRPC biopsy biomarker expression. Overall, CCS1477 shows promise for the treatment of patients with advanced prostate cancer. SIGNIFICANCE: Treating CRPC remains challenging due to persistent AR signaling. Inhibiting transcriptional AR coactivators is an attractive therapeutic strategy. CCS1477, an inhibitor of p300/CBP, inhibits growth and AR activity in CRPC models, and can affect metastatic CRPC target expression in serial clinical biopsies...

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