Novel Insights into Molecular Indicators of Response and Resistance to Modern Androgen-Axis Therapies in Prostate Cancer

Curr Urol Rep. 2016 Apr;17(4):29. doi: 10.1007/s11934-016-0584-4.

Abstract

While androgen ablation remains a mainstay for advanced prostate cancer therapy, nearly all patients will inevitably develop disease escape with time. Upon the development of castration-resistant prostate cancer, other androgen-axis-targeted treatments may be added in an effort to starve the disease of its androgen signaling. Nevertheless, additional androgen-pathway resistance usually develops to these novel hormonal therapies. In this review, we will discuss the resistance mechanisms to modern androgen-axis modulators and how these alterations can influence a patient's response to novel hormonal therapy. We conceptualize these resistance pathways as three broad categories: (1) reactivation of androgen/AR-signaling, (2) AR bypass pathways, and (3) androgen/AR-independent mechanisms. We highlight examples of each, as well as potential therapeutic approaches to overcome these resistance mechanisms.

Keywords: Androgen receptor; Biomarker; Prostate cancer; Resistance; Splice variants.

Publication types

  • Review

MeSH terms

  • Alternative Splicing
  • Androgen Antagonists / therapeutic use
  • Androgens / metabolism*
  • Animals
  • Drug Resistance, Neoplasm*
  • Humans
  • Male
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Receptors, Androgen / metabolism
  • Signal Transduction / drug effects

Substances

  • Androgen Antagonists
  • Androgens
  • Receptors, Androgen