The Role of Epigenetic Change in Therapy-Induced Neuroendocrine Prostate Cancer Lineage Plasticity

Abstract

The androgen receptor (AR) signaling pathway is critical for growth and differentiation of prostate cancer cells. For that reason, androgen deprivation therapy with medical or surgical castration is the principal treatment for metastatic prostate cancer. More recently, new potent AR signaling inhibitors (ARSIs) have been developed. These drugs improve survival for men with metastatic castration-resistant prostate cancer (CRPC), the lethal form of the disease. However, ARSI resistance is nearly universal. One recently appreciated resistance mechanism is lineage plasticity or switch from an AR-driven, luminal differentiation program to an alternate differentiation program. Importantly, lineage plasticity appears to be increasing in incidence in the era of new ARSIs, strongly implicating AR suppression in this process. Lineage plasticity and shift from AR-driven tumors occur on a continuum, ranging from AR-expressing tumors with low AR activity to AR-null tumors that have activation of alternate differentiation programs versus the canonical luminal program found in AR-driven tumors. In many cases, AR loss coincides with the activation of a neuronal program, most commonly exemplified as therapy-induced neuroendocrine prostate cancer (t-NEPC). While genetic events clearly contribute to prostate cancer lineage plasticity, it is also clear that epigenetic events-including chromatin modifications and DNA methylation-play a major role. Many epigenetic factors are now targetable with drugs, establishing the importance of clarifying critical epigenetic factors that promote lineage plasticity. Furthermore, epigenetic marks are readily measurable, demonstrating the importance of clarifying which measurements will help to identify tumors that have undergone or are at risk of undergoing lineage plasticity. In this review, we discuss the role of AR pathway loss and activation of a neuronal differentiation program as key contributors to t-NEPC lineage plasticity. We also discuss new epigenetic therapeutic strategies to reverse lineage plasticity, including those that have recently entered clinical trials.

Keywords: Androgen Receptor (AR); Lineage plasticity; Neuroendocrine prostate cancer (NEPC); epigenetics; transdifferentiation.

Figure 1

Overview of selected molecular events that contribute to the transition from adenocarcinoma to neuroendocrine prostate cancer. Loss of a canonical AR signaling program and activation of a neuronal or neuroendocrine program are hallmarks of the transition from adenocarcinoma to neuroendocrine prostate cancer. Treatment with AR signaling inhibitors (ARSIs) results in suppression of canonical AR signaling and activation of AR-repressed genes linked with a neuronal or neuroendocrine program in some tumors. Loss of REST’s repressive activity promotes NEPC lineage plasticity, in part through activation of the nBAF chromatin remodeling complex. EZH2 has been shown to silence AR expression by catalyzing H3K27me3 at the AR promoter. Phosphorylation of the T350 residue on EZH2 results in reprograming of the AR cistrome and activation of stemness or neuronal genes. Loss of the chromatin remodeling factor CHD1 results in redistribution of the AR away from canonical AR target genes to tumor-specific AR-bound regions. CHD1 loss also increases chromatin accessibility for the neuronal transcription factor POU3F2 that may contribute to activation of the stemness factor SOX2. The HDAC SIRT1 promotes NEPC lineage plasticity, potentially through activation of SOX2. PTEN, RB1, and TP53 are commonly altered in NEPC, and their loss promotes activation of a neuronal program in part through activation of E2F1 or SOX2. E2F1 has been shown to cooperate with DNA methyltransferases to silence the AR through AR promoter DNA methylation. E2F1 also cooperates with LSD1 or BET bromodomain chromatin readers to activate a cell cycle or neuronal program. Factors that are currently targetable with drugs that are approved by the Food & Drug Administration or that are in clinical trials are shown in red. Created with BioRender.com.