Resistance to BET Inhibitor Leads to Alternative Therapeutic Vulnerabilities in Castration-Resistant Prostate Cancer

Abstract

BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration-resistant prostate cancer (CRPC). Several BET inhibitors (BETi) that displace BRD4 from chromatin are being evaluated in clinical trials for CRPC. Here, we describe mechanisms of acquired resistance to BETi that are amenable to targeted therapies in CRPC. BETi-resistant CRPC cells displayed cross-resistance to a variety of BETi in the absence of gatekeeper mutations, exhibited reduced chromatin-bound BRD4, and were less sensitive to BRD4 degraders/knockdown, suggesting a BRD4-independent transcription program. Transcriptomic analysis revealed reactivation of AR signaling due to CDK9-mediated phosphorylation of AR, resulting in sensitivity to CDK9 inhibitors and enzalutamide. Additionally, increased DNA damage associated with PRC2-mediated transcriptional silencing of DDR genes was observed, leading to PARP inhibitor sensitivity. Collectively, our results identify the therapeutic limitation of BETi as a monotherapy; however, our BETi resistance data suggest unique opportunities for combination therapies in treating CRPC.

Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer

“…This resistance may be prevented by the use of BET degraders instead of BET inhibitors, and may indicate that sequential treatment is not necessarily beneficial. CDK9 activation also promotes PRC2 activity and silences DNA damage repair genes to promote DNA damage and sensitize cells to PARP inhibitors and chemotherapeutics (48). Outside of the strong preclinical data presented here, evidence strongly suggests combination therapies of PARP inhibitors, platinum-based drugs, AR antagonists, and immunotherapies with BET degraders are worth investigating for treatment of CRPC.…”

“…BET degradation has also been shown to decrease transcription globally in a manner that phenocopies cyclin-dependent kinase 9 (CDK9) inhibition, and CDK9 hyperphosphorylation and activity have been shown to promote resistance to BET inhibitors as well (48). This resistance may be prevented by the use of BET degraders instead of BET inhibitors, and may indicate that sequential treatment is not necessarily beneficial.…”

Chromatin reprogramming as an adaptation mechanism in advanced prostate cancer

“…Mechanisms of resistance to BETi have been already reported (Rathert et al 2015) and are probably due to compensatory mechanisms still linked to chromatin reprogramming which are capable of activating alternative oncogenic pathways (Pawar et al 2018). Therefore, targeting a deregulated chromatin structure with BETi is an attractive therapeutic strategy as it is plausible that chromatin deregulation is a reversible mechanism.…”

BETter together: exploiting BRD4-functions in transcription to inform rational combinations

“…This complexity underlying transcriptional plasticity and re-wiring following BET inhibition was also highlighted by another recent study [8]. Prostate cancer cells made resistant to BETi by extended JQ1 treatment were exquisitely sensitive to either CDK9 or PARP1 inhibition, unlike their parental cells.…”