Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer.

Neel Shah,Deyou Zheng,Henry W Long,Ping Wang,Matthew L Freedman,Charles L Sawyers,Joshua Armenia,Vivek K Arora,Yotam Drier,Wassim Abida,John Wongvipat,Shira Rockowitz,Bradley E Bernstein,Wouter R Karthaus

doi:10.7554/elife.27861

Abstract

In prostate cancer, resistance to the antiandrogen enzalutamide (Enz) can occur through bypass of androgen receptor (AR) blockade by the glucocorticoid receptor (GR). In contrast to fixed genomic alterations, here we show that GR-mediated antiandrogen resistance is adaptive and reversible due to regulation of GR expression by a tissue-specific enhancer. GR expression is silenced in prostate cancer by a combination of AR binding and EZH2-mediated repression at the GR locus, but is restored in advanced prostate cancers upon reversion of both repressive signals. Remarkably, BET bromodomain inhibition resensitizes drug-resistant tumors to Enz by selectively impairing the GR signaling axis via this enhancer. In addition to revealing an underlying molecular mechanism of GR-driven drug resistance, these data suggest that inhibitors of broadly active chromatin-readers could have utility in nuanced clinical contexts of acquired drug resistance with a more favorable therapeutic index.

Highlights

Drugs targeting the androgen receptor (AR) signaling pathway form the backbone of therapy for advanced prostate cancer
The importance of glucocorticoid receptor (GR) as a resistance mechanism was evident in the castration-resistant prostate cancer (CRPC) organoid line (MSK-PCa2) (Gao et al, 2014), where dexamethasone (Dex) treatment partially restored growth and rescued AR target gene expression in the presence of Enz (Figure 1—figure supplement 1B,C)
This report provides new mechanistic insight into how GR expression is restored in a subset of CRPC patients with acquired resistance to Enz, and how BET inhibitors can have surprisingly selective effects on gene expression in specific contexts

Summary

Introduction

Drugs targeting the androgen receptor (AR) signaling pathway form the backbone of therapy for advanced prostate cancer. Despite initial responses to androgen deprivation therapy (ADT), patients with metastatic disease invariably progress to a stage termed castration-resistant prostate cancer (CRPC). Overall survival of CRPC patients is significantly improved by treatment with generation AR pathway inhibitors such as abiraterone (Abi) and enzalutamide (Enz) that more effectively target. Cancer Biology the AR signaling axis (Scher et al, 2012; de Bono et al, 2011). Acquired resistance to these drugs is a major clinical problem

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Conclusion