Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer

Abstract

Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. The development and progression to CRPC following androgen ablation therapy is predominantly driven by unregulated androgen receptor (AR) signaling1-3. Despite the success of recently approved therapies targeting AR signaling such as abiraterone4-6 and second generation anti-androgens MDV3100 (enzalutamide)7,8, durable responses are limited, presumably due to acquired resistance. Recently JQ1 and I-BET, two selective small molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit anti-proliferative effects in a range of malignancies9-12. Here we show that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ111,13. Like the direct AR antagonist, MDV3100, JQ1 disrupted AR recruitment to target gene loci. In contrast to MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR-mediated gene transcription including induction of TMPRSS2-ERG and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer.

Disruption of BRD4 at H3K27Ac-enriched enhancer region correlates with decreased c-Myc expression in Merkel cell carcinoma

“…8 Furthermore, inhibition of BET bromodomain by small-molecule compounds with high potency against BET proteins, such as JQ1, results in significant downregulation of c-Myc as well as other transcription factors, and display antitumor activity in a variety of preclinical animal models of human cancers. [9][10][11][12] Importantly, these studies have established the feasibility of BET inhibition within an acceptable therapeutic window of tolerability. As a result, similar small molecules are currently in Phase I clinical trial for haematopoietic malignancies and advanced solid tumors (ClinicalTrials.…”

BETs abet Tam-R in ER-positive breast cancer

“…The effectiveness of BET inhibitors in tamoxifen-resistant breast cancer parallels our recent report of their effectiveness in castration-resistant prostate cancer (CRPC) [6], which analogous to tamoxifen-resistant ER-positive breast cancer, continues to maintain steroid hormone dependence. We have shown that the N-terminal region of BRD2/3/4 containing the BD1-BD2 domains physically interacts with the N-terminus of the Androgen Receptor (AR) and that this interaction is disrupted by JQ1.…”

Treatment of metastatic prostate cancer

“…Examples of these include BET inhibitors, recently demonstrated to be effective in pre-clinical models of CRPC and antisense oligonucleotides, capable of inhibiting AR-mediated DNA transcription, currently in early phase clinical trials (NCT02122051). 22,23 Increased understanding of the interaction between AR and other oncological pathways, such as the PI3K-PTEN-AKT pathway, provides another rationale for alterative therapeutic approaches. PTEN loss is seen in around 40% of CRPC patients and is associated with shorter overall survival and earlier treatment failure with abiraterone.…”