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Supplementary Figure S3 from BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program

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posted on 2023-03-31, 22:51 authored by 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, Arvind Rao, Emily M. Gesner, Sarah Attwell, Sanjay Lakhotia, Eric Campeau, Joel A. Yates, Zheng Xia, Joshi J. Alumkal
Supplementary Figure S3 from BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program

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National Cancer Institute (NCI)

United States Department of Health and Human Services

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Cancer Moonshot (Misión contra el Cáncer)

DOD Prostate Cancer Research Program (PCRP)

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ARTICLE ABSTRACT

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

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    Clinical Cancer Research

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    cancer

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