Exploitation of Castration-Resistant Prostate Cancer Transcription Factor Dependencies by the Novel BET Inhibitor ABBV-075

Competitive inhibitors targeting acetyl-lysine binding to the bromodomains of the BET (bromodomain and extra-terminal) family are being developed for the treatment of both solid and hematologic cancers. The BET family member BRD4 plays a key role at enhancers and superenhancers, maintaining signal-dependent or pathogenic gene expression programs. This study tested the hypothesis that transcription factors involved in the clinical progression of castration-resistant prostate cancer (CRPC), including the androgen receptor (AR), are critically dependent on BRD4, making them sensitive to the BET inhibitor ABBV-075. ABBV-075 inhibited DHT-stimulated transcription of AR target genes without significantly affecting AR protein levels. Additionally, it disrupted the DHT-stimulated recruitment of BRD4 to gene-regulatory regions co-occupied by AR, including well-established PSA and TMPRSS2 enhancers. Continued BET inhibition altered the composition and function of AR-bound enhancers, evidenced by reduced AR and H3K27Ac ChIP signals and decreased enhancer RNA transcription. ABBV-075 showed strong antiproliferative activity in multiple models of resistance to second-generation antiandrogens and inhibited the AR splice variant AR-V7 as well as gain-of-function mutations in the AR ligand-binding domain (F877L and L702H). Furthermore, ABBV-075 effectively inhibited MYC and the TMPRSS2-ETS fusion protein, Mivebresib both of which are important parallel transcription factor drivers in CRPC.