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

Autor:	Kim DH; Knight Cancer Institute, Oregon Health & Science University (OHSU), Portland, Oregon., Sun D; Knight Cancer Institute, Oregon Health & Science University (OHSU), Portland, Oregon., Storck WK; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan., Welker Leng K; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan., Jenkins C; Knight Cancer Institute, Oregon Health & Science University (OHSU), Portland, Oregon., Coleman DJ; Knight Cancer Institute, Oregon Health & Science University (OHSU), Portland, Oregon., Sampson D; Knight Cancer Institute, Oregon Health & Science University (OHSU), Portland, Oregon., Guan X; Knight Cancer Institute, Oregon Health & Science University (OHSU), Portland, Oregon., Kumaraswamy A; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan., Rodansky ES; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan., Urrutia JA; Knight Cancer Institute, Oregon Health & Science University (OHSU), Portland, Oregon., Schwartzman JA; Knight Cancer Institute, Oregon Health & Science University (OHSU), Portland, Oregon., Zhang C; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan., Beltran H; Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts., Labrecque MP; Department of Urology, University of Washington, Seattle, Washington., Morrissey C; Department of Urology, University of Washington, Seattle, Washington., Lucas JM; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington., Coleman IM; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington., Nelson PS; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington., Corey E; Department of Urology, University of Washington, Seattle, Washington., Handelman SK; Center for Drug Repurposing, Department of Internal Medicine, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan., Sexton JZ; Center for Drug Repurposing, Department of Internal Medicine, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan., Aggarwal R; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California., Abida W; Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Feng FY; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California., Small EJ; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California., Spratt DE; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan.; Department of Radiation Oncology, University Hospitals, Case Western Reserve University, Cleveland, Ohio., Bankhead A 3rd; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan.; Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, Michigan.; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan., Rao A; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan.; Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, Michigan.; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan., Gesner EM; Zenith Epigenetics Ltd, Calgary, Alberta, Canada., Attwell S; Zenith Epigenetics Ltd, Calgary, Alberta, Canada., Lakhotia S; Zenith Epigenetics Ltd, Calgary, Alberta, Canada., Campeau E; Zenith Epigenetics Ltd, Calgary, Alberta, Canada., Yates JA; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan., Xia Z; Knight Cancer Institute, Oregon Health & Science University (OHSU), Portland, Oregon. jalumkal@med.umich.edu xiaz@ohsu.edu., Alumkal JJ; Knight Cancer Institute, Oregon Health & Science University (OHSU), Portland, Oregon. jalumkal@med.umich.edu xiaz@ohsu.edu.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Sep 01; Vol. 27 (17), pp. 4923-4936. Date of Electronic Publication: 2021 Jun 18.
DOI:	10.1158/1078-0432.CCR-20-4968
Abstrakt:	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. (©2021 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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