Details

Autor(en) / Beteiligte

• Kim, Dae-Hwan
• Sun, Duanchen
• Storck, William K
• Welker Leng, Katherine
• Jenkins, Chelsea
• Coleman, Daniel J
• Sampson, David
• Guan, Xiangnan
• Kumaraswamy, Anbarasu
• Rodansky, Eva S
• Urrutia, Joshua A
• Schwartzman, Jacob A
• Zhang, Chao
• Beltran, Himisha
• Labrecque, Mark P
• Morrissey, Colm
• Lucas, Jared M
• Coleman, Ilsa M
• Nelson, Peter S
• Corey, Eva
• Handelman, Samuel K
• Sexton, Jonathan Z
• Aggarwal, Rahul
• Abida, Wassim
• Feng, Felix Y
• Small, Eric J
• Spratt, Daniel E
• Bankhead, 3rd, Armand
• Rao, Arvind
• Gesner, Emily M
• Attwell, Sarah
• Lakhotia, Sanjay
• Campeau, Eric
• Yates, Joel A
• Xia, Zheng
• Alumkal, Joshi J

Titel

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

Ist Teil von

• Clinical cancer research, 2021-09, Vol.27 (17), p.4923-4936

Ort / Verlag

United States

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 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.