Somatic Alterations Impact AR Transcriptional Activity and Efficacy of AR-Targeting Therapies in Prostate Cancer.

Gaurav Chauhan,Hannelore V Heemers

doi:10.3390/cancers13163947

Abstract

Simple SummaryFor patients whose prostate cancer spreads beyond the confines of the prostate, treatment options continue to increase. However, we are missing the information that is needed to choose for each patient the best treatment at each step of his cancer progression so we can ensure that maximal remissions and prolonged survival are achieved. In this review, we examine whether a better understanding of how the activity of the target for the default first treatment, the androgen receptor, is regulated in prostate cancer tissues can improve prostate cancer treatment plans. We consider the evidence for variability of androgen receptor activity among patients and examine the molecular basis for this variable action. We summarize clinical evidence supporting that information on a prostate cancer’s genomic composition may inform on its level of androgen receptor action, which may facilitate choice for the most effective first-line therapy and ultimately improve prostate cancer treatment plans overall.Inhibiting the activity of the ligand-activated transcription factor androgen receptor (AR) is the default first-line treatment for metastatic prostate cancer (CaP). Androgen deprivation therapy (ADT) induces remissions, however, their duration varies widely among patients. The reason for this heterogeneity is not known. A better understanding of its molecular basis may improve treatment plans and patient survival. AR’s transcriptional activity is regulated in a context-dependent manner and relies on an interplay between its associated transcriptional regulators, DNA recognition motifs, and ligands. Alterations in one or more of these factors induce shifts in the AR cistrome and transcriptional output. Significant variability in AR activity is seen in both castration-sensitive (CS) and castration-resistant CaP (CRPC). Several AR transcriptional regulators undergo somatic alterations that impact their function in clinical CaPs. Some alterations occur in a significant fraction of cases, resulting in CaP subtypes, while others affect only a few percent of CaPs. Evidence is emerging that these alterations may impact the response to CaP treatments such as ADT, radiation therapy, and chemotherapy. Here, we review the contribution of recurring somatic alterations on AR cistrome and transcriptional output and the efficacy of CaP treatments and explore strategies to use these insights to improve treatment plans and outcomes for CaP patients.

Highlights

Prostate cancer (CaP) remains the most frequently diagnosed non-skin cancer and the second leading cause of cancer-related mortality in American men [1]
The acquired resistance that almost invariably occurs following an initial remission by androgen deprivation therapy (ADT) is a major contributor to the more than 30,000 CaP deaths that occur in the United States each year [4,6,7,8,9]
Newer and more potent androgen biosynthesis inhibitors or antiandrogens that were developed as second-line Androgen deprivation therapy (ADT) to overcome androgen receptor (AR)-dependent growth of castration-resistant CaP (CRPC) that emerges after the failure of traditional, first-line ADT drugs, are increasingly administered earlier in ADT-naïve or castration-sensitive CaP (CS-CaP) [2,11,12]

Summary

Introduction

Prostate cancer (CaP) remains the most frequently diagnosed non-skin cancer and the second leading cause of cancer-related mortality in American men [1]. Newer and more potent androgen biosynthesis inhibitors (e.g., abiraterone acetate, usually taken with prednisone) or antiandrogens (e.g., enzalutamide, apalutamide, darolutamide) that were developed as second-line ADT to overcome AR-dependent growth of castration-resistant CaP (CRPC) that emerges after the failure of traditional, first-line ADT drugs, are increasingly administered earlier in ADT-naïve or castration-sensitive CaP (CS-CaP) [2,11,12] Throughout this manuscript, we will refer to CS-CaP as CaP that has not yet been exposed to ADT and is ADT-responsive, whereas the term CRPC will be used to designate CaP that has recurred after at least one round of ADT. Androgen binding to LBD activates AR and causes its re-localization from the cytoplasm to the cell nucleus where AR binds as a dimer to consensus DNA binding motifs known as Androgen Response Elements (AREs) to exert control over transcription of target genes. Tthhaits wstarsucintucurablaitnedforinmvaittiroonwwitahs roeblata-ined tuivseinlygsrmecaollmDbNinAasnetqAueRntcheas tspwaansnincguabcaotnedseinnsuvsitAroRwE i(t3h2 rbepl)atoirvaelDyNsmAarlelgDioNnA(32s4eqbupe)nces esnpcaonmnpinagssaincgonAsRenEsufsouAnRdEin(3t2hebpen) hoarnacDerNreAgiroengioofnth(3e2g4ebnpe)-eennccoodminpgaPssSiAng[3A6R].EPsSfAouisnd in athweeelln-shtaundciedr rAegRiotanrgoefttgheengeewneh-oesnecsoedriunmg PleSvAels[3a6r]e. rPoSuAtiniselay wmeelals-sutrueddieads aAsRurtraorggaettegene fworhaospeastieernutm’s CleavPelbsuarrdeenro[u3t7i]n. eInlyclmuseiaosnuoref dreacsoma bsuinrarnotgapt3e00foarnadpSaRtiCe-n3t’psrCotaePinbiunrcdreyn- [37]. oInEcMluasisosnayosf srheocowmedbinthaanttipn3te0r0- aanndd SinRtCra-3-mporloetceuinlairnNcr/CyoiEnMterascstiaoynsssohfowARedmthoantoimnteerrs- and fianctirlait-amteoalelscouilnatreNra/ctCioinntseitreascftoiorntsheosfeAARRm-asosnoocmiateerds cfaocrielgitualtaetoarlsothinattearraecqtiuointesditieffsefroenr tthese fAroRm-atshsoosceiaftoeudncdofroergoutlhaetor rNsRthsa[t36a]r.e quite different from those found for other NRs [36]

Determinants of AR Transcriptional Output and Target Gene Expression

Molecular Basis for Differences in AR Action among Clinical CaP

Findings

Future Directions