1. Academic Validation
  2. Resistance to BET Inhibitor Leads to Alternative Therapeutic Vulnerabilities in Castration-Resistant Prostate Cancer

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

  • Cell Rep. 2018 Feb 27;22(9):2236-2245. doi: 10.1016/j.celrep.2018.02.011.
Aishwarya Pawar 1 Paradesi Naidu Gollavilli 1 Shaomeng Wang 2 Irfan A Asangani 3
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 2 Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA.
  • 3 Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cancer Biology, Abramson Family Cancer Research Institute, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA. Electronic address: asangani@upenn.edu.
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.

Keywords

AR; BET inhibitors; BRCAness; CDK9; DNA damage; PARP inhibitors; acquired drug resistance; chromatin; prostate cancer.

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