Genetic Profiling of Glucocorticoid (NR3C1) and Mineralocorticoid (NR3C2) Receptor Polymorphisms before Starting Therapy with Androgen Receptor Inhibitors: A Study of a Patient Who Developed Toxic Myocarditis after Enzalutamide Treatment

Abstract

Enzalutamide is a nonsteroidal inhibitor of the androgen receptor (AR) signaling pathway and is used to treat patients with metastatic castration-resistant prostate cancer. However, the risk of cardiovascular-related hospitalization in patients with no contraindications for the use of enzalutamide is about 1-2%. To date, the underlying molecular basis of this has not been established. The androgen receptor, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are nuclear receptors that share structural similarities and have closely related DNA-binding sites and coregulators. In non-epithelial cells, a fine balance of the activities of these receptors is essential to ensure correct cellular function. In this study, we present a molecular characterization of these nuclear receptors in a prostate cancer patient who developed congestive heart failure after enzalutamide treatment. White cell RNAseq revealed a homozygous rs5522 MR polymorphism and both the rs143711342 and rs56149945 GR polymorphisms, carried in different alleles. No different specific splice isoforms were detected. Recent research suggests that AR inhibition by enzalutamide makes available a coregulator that specifically interacts with the rs5522-mutated MR, increasing its activity and producing adverse effects on cardiovascular health. We suggest an evaluation of the MR rs5522 polymorphism before starting therapy with AR inhibitors.

Keywords: aldosterone; androgen receptor; androgen receptor inhibitors; enzalutamide; glucocorticoid receptor; mineralocorticoid receptor; prostate cancer; spironolactone; toxic myocarditis.

Figure 1

Schematic representation of the protein isoforms expressed by both alleles of MR (NR3C2) and GR (NR3C1) genes in the patient. NTD, N-terminal domain; DBD, DNA-binding domain; H, hinge region; LBD, ligand-binding domain; AF1/AF2, activating function domains 1/2.

Figure 2

Predicted splice graph and splice junction expression for NR3C1 (A) and NR3C2 (B). Heatmaps are based on splice junction expression on a log2(FPKM + 1) scale. Grey boxes indicate annotated transcript features. Introns are not drawn to scale.

Figure 3

GR, MR and AR signaling pathways in non-epithelial cells. (A) Balanced transcriptional activation signaling pathways with normal receptors. (B) Increased activation of the MR signaling pathway with expression of MR rs5522 and GR rs143711342/rs56149945. (C) Pathological effects of AR inhibition by enzalutamide on the MR signaling pathway in cells expressing MR rs5522 and GR rs143711342/rs56149945.