BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program

Clin Cancer Res. 2021 Sep 1;27(17):4923-4936. doi: 10.1158/1078-0432.CCR-20-4968. Epub 2021 Jun 18.

Abstract

Purpose: Lineage plasticity in prostate cancer-most commonly exemplified by loss of androgen receptor (AR) signaling and a switch from a luminal to alternate differentiation program-is now recognized as a treatment resistance mechanism. Lineage plasticity is a spectrum, but neuroendocrine prostate cancer (NEPC) is the most virulent example. Currently, there are limited treatments for NEPC. Moreover, the incidence of treatment-emergent NEPC (t-NEPC) is increasing in the era of novel AR inhibitors. In contradistinction to de novo NEPC, t-NEPC tumors often express the AR, but AR's functional role in t-NEPC is unknown. Furthermore, targetable factors that promote t-NEPC lineage plasticity are also unclear.

Experimental design: Using an integrative systems biology approach, we investigated enzalutamide-resistant t-NEPC cell lines and their parental, enzalutamide-sensitive adenocarcinoma cell lines. The AR is still expressed in these t-NEPC cells, enabling us to determine the role of the AR and other key factors in regulating t-NEPC lineage plasticity.

Results: AR inhibition accentuates lineage plasticity in t-NEPC cells-an effect not observed in parental, enzalutamide-sensitive adenocarcinoma cells. Induction of an AR-repressed, lineage plasticity program is dependent on activation of the transcription factor E2F1 in concert with the BET bromodomain chromatin reader BRD4. BET inhibition (BETi) blocks this E2F1/BRD4-regulated program and decreases growth of t-NEPC tumor models and a subset of t-NEPC patient tumors with high activity of this program in a BETi clinical trial.

Conclusions: E2F1 and BRD4 are critical for activating an AR-repressed, t-NEPC lineage plasticity program. BETi is a promising approach to block this program.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androgen Receptor Antagonists / therapeutic use*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use*
  • Benzamides / therapeutic use*
  • Carcinoma, Neuroendocrine / drug therapy*
  • Cell Line, Tumor
  • E2F1 Transcription Factor / drug effects*
  • E2F1 Transcription Factor / physiology*
  • Humans
  • Male
  • Nitriles / therapeutic use*
  • Phenylthiohydantoin / therapeutic use*
  • Prostatic Neoplasms / drug therapy*
  • Proteins / antagonists & inhibitors*

Substances

  • Androgen Receptor Antagonists
  • Antineoplastic Agents
  • Benzamides
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • Nitriles
  • Proteins
  • bromodomain and extra-terminal domain protein, human
  • Phenylthiohydantoin
  • enzalutamide