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

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.

• Authors: Dae-Hwan Kim, Duanchen Sun, William K Storck, Katherine Welker Leng, Chelsea Jenkins, Daniel J Coleman, David Sampson, Xiangnan Guan, Anbarasu Kumaraswamy, Eva S Rodansky, Joshua A Urrutia, Jacob A Schwartzman, Chao Zhang, Himisha Beltran, Mark P Labrecque, Colm Morrissey, Jared M Lucas, Ilsa M Coleman, Peter S Nelson, Eva Corey, Samuel K Handelman, Jonathan Z Sexton, Rahul Aggarwal, Wassim Abida, Felix Y Feng, Eric J Small, Daniel E Spratt, Armand Bankhead 3rd, Arvind Rao, Emily M Gesner, Sarah Attwell, Sanjay Lakhotia, Eric Campeau, Joel A Yates, Zheng Xia, Joshi J Alumkal
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 17 Pg. 4923-4936 (09 01 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 34145028 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

Chemical References

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

Topics

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