Development and prevalence of castration-resistant prostate cancer subtypes

Neoplasia. 2020 Nov;22(11):566-575. doi: 10.1016/j.neo.2020.09.002. Epub 2020 Sep 25.

Abstract

Background: Castration-resistant prostate cancer (CRPC) occurs when prostate cancer (CaP) progresses under therapy-induced castrate conditions. Several mechanisms have been proposed to explain this acquired resistance, many of which are driven by androgen receptor (AR). Recent findings, however, sub-classified CRPC by downregulation/absence of AR in certain subtypes that consequently do not respond to anti-androgen therapies. To highlight the significance of CRPC sub-classification, we reviewed the development and treatment of CRPC, AR downregulation in CRPC, and summarized recent reports on the prevalence of CRPC subtypes.

Methods: Using a medline-based literature search, we reviewed mechanisms of CRPC development, current treatment schemes, and assessed the prevalence of AR low/negative subtypes of CRPC. Additionally, we performed immunohistochemical staining on human CRPC specimens to quantify AR expression across CRPC subtypes.

Results: In the majority of cases, CRPC continues to rely on AR signaling, which can be augmented in castrate-conditions through a variety of mechanisms. However, recently low/negative AR expression patterns were identified in a significant proportion of patient samples from a multitude of independent studies. In these AR low/negative cases, we postulated that AR protein may be downregulated by (1) promoter methylation, (2) transcriptional regulation, (3) post-transcriptional regulation by microRNA or RNA-binding-proteins, or (4) post-translational ubiquitination-mediated degradation.

Conclusions: Here, we discussed mechanisms of CRPC development and summarized the overall prevalence of CRPC subtypes; interestingly, AR low/negative CRPC represented a considerable proportion of diagnoses. Because these subtypes cannot be effectively treated with AR-targeted therapeutics, a better understanding of AR low/negative subtypes could lead to better treatment strategies and increased survival.

Keywords: AR low prostate cancer; Castration-resistant prostate cancer; Double negative prostate cancer; Neuroendocrine prostate cancer; Therapy resistance.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Androgens / metabolism
  • Antineoplastic Agents / pharmacology
  • Biomarkers
  • Disease Management
  • Disease Susceptibility*
  • Humans
  • Immunohistochemistry
  • Male
  • Molecular Targeted Therapy
  • Neoplasm Grading
  • Neoplasm Staging
  • Prevalence
  • Prostatic Neoplasms, Castration-Resistant / diagnosis*
  • Prostatic Neoplasms, Castration-Resistant / etiology*
  • Prostatic Neoplasms, Castration-Resistant / metabolism
  • Prostatic Neoplasms, Castration-Resistant / therapy
  • Receptors, Androgen / metabolism
  • Signal Transduction / drug effects

Substances

  • AR protein, human
  • Androgens
  • Antineoplastic Agents
  • Biomarkers
  • Receptors, Androgen