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.

Jumonji domain-containing protein RIOX2 is overexpressed and associated with worse survival outcomes in prostate cancers

“…Over the last two decades, genetic and epigenetic alterations have been identified as oncogenic drivers to modulate AR-dependent cistrome reprogramming during prostate cancer development, progression, and treatment resistance (30)(31)(32). Several epigenetic modifiers were identified as prostate cancer biomarkers, including histone demethylases (33).…”

Treatment-related Neuroendocrine Prostate Carcinoma—Diagnostic and Molecular Correlates

“…Concomitant with reduction in AR, an increasing body of evidence points to a constellation of molecular events associated with transition from adenocarcinoma to the neuroendocrine phenotype, which includes genetic alterations in key tumor suppressor genes TP53, RB1, and PTEN; epigenetic reprogramming; dysregulation of transcription factors SOX2, achaete-scute-homolog 1 (ASCL1), BRN2, FOAXA1, FOXA2, and ONECUT2; upregulation of oncogenes N-MYC and Aurora Kinase A (AURKA); and epithelial-mesenchymal transition. [31][32][33] The following sections highlight key genes and molecular events, which are among several that drive or facilitate lineage plasticity, neuroendocrine tumor development, and proliferation in a complex orchestration (Fig. 1).…”

“…Expression of DNA methyltransferase DNMT1 is increased in prostate epithelium with RB1 loss, which negatively regulates the transcription factor E2F1, which increases DMNT1 expression. 33 More than a fifth of castration-resistant prostate carcinoma metastases exhibit DNA hypermethylation, which is associated with the RNA expression of AR, MYC, and ERG. 47 Hypermethylation of INSM1 and the plasticity marker CDH2 has been observed in cell-free DNA samples from patients with adenocarcinoma, which transform to NEPC.…”

Comprehensive data mining reveals RTK/RAS signaling pathway as a promoter of prostate cancer lineage plasticity through transcription factors and CNV

“…Specific SWI/SNF complexes are associated with PCa progression and may play a role in treatment resistance 12 . Moreover, epigenetic factors such as chromatin modifications and DNA methylation also play a role in promoting lineage plasticity 13 . Indeed, lineage plasticity is not confined to prostate cancer, as this phenomenon has been noted in both lung and breast cancer 14 , 15 .…”