BET bromodomain inhibition blocks an AR-repressed, E2F1-activated treatment-emergent neuroendocrine prostate cancer lineage plasticity program

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 CoreySamuel K. Handelman, Jonathan Z. Sexton, Rahul Aggarwal, Wassim Abida, Felix Y. Feng, Eric J. Small, Daniel E. Spratt, Armand Bankhead, Arvind Rao, Emily M. Gesner, Sarah Attwell, Sanjay Lakhotia, Eric Campeau, Joel A. Yates, Zheng Xia, Joshi J. Alumkal

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 ARrepressed, t-NEPC lineage plasticity program. BETi is a promising approach to block this program.

Original languageEnglish (US)
Pages (from-to)4923-4936
Number of pages14
JournalClinical Cancer Research
Volume27
Issue number17
DOIs
StatePublished - Sep 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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