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/BRD4regulated 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.Research.

ASCL1 activates neuronal stem cell-like lineage programming through remodeling of the chromatin landscape in prostate cancer

“…CRPC (16D CRPC ) and ENZ-resistant AR+ NE-like (42D ENZR ) cell lines were generated from LNCaP cells, previously detailed by our group 31 , 54 . We utilized an in vivo model of CRPC and ENZ resistance previously developed by us 31 , 54 , 55 that mirrors clinically reported treatment refractory phenotypes. LNCaP cells were inoculated into mice and upon castration CRPC tumors (16D CRPC ) emerged.…”

Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective

“…However, with the widespread use of Enzalutamide and Abiraterone, a subset of CRPC patients developed neuroendocrine progression, termed as anti-AR treatmentinduced NEPC (t-NEPC) (72,73), accounting for more than 25-30% mortality of CRPC fatality (74). There were multiple mechanisms involved in NEPC progression, including attenuated control of transcriptional factors, metabolic alterations, aberrant activation of cellular kinases, long noncoding RNAs, transcriptional splicing, and epigenetic modifications (75)(76)(77)(78)(79)(80)(81)(82)(83)(84)(85)(86)(87). It is postulated that extensive stress of AR inhibition under the long-term ADT condition forced an epigenetic reprogramming of CRPC cells into neuroendocrinal trans-differentiation (88)(89)(90)(91)(92)(93).…”

From Therapy Resistance to Targeted Therapies in Prostate Cancer

“…In therapy resistant PCa, histone acetyltransferases (HATs), HDACs, histone demethylases (HDMs), histone methyltransferases (HMTs), BET, and DNMTs inhibitors are currently under pre-clinical and clinical studies ( Table 2 and Supplementary Table 2 ), displaying anti-tumoral effects, mostly due to enzyme inhibition and gene expression reprograming ( Supplementary Table 2 ). Interestingly, the most promising results were found when epi-drugs were combined with standard ADT compounds ( 188 , 209 , 224 , 228 , 229 , 241 , 243 ), docetaxel ( 175 , 197 , 210 , 217 , 234 ), radiation therapy ( 203 ) or other epi-drugs ( 196 , 204 , 235 ), suggesting an interplay between epigenetic and non-epigenetic targeting in PCa management.…”