Recent Discoveries in the Androgen Receptor Pathway in Castration-Resistant Prostate Cancer

Daisuke Obinata, Mitchell G. Lawrence, Kenichi Takayama, Nicholas Choo, Gail P. Risbridger, Satoru Takahashi, Satoshi Inoue

Research output: Contribution to journalReview ArticleResearchpeer-review

Abstract

The androgen receptor (AR) is the main therapeutic target in advanced prostate cancer, because it regulates the growth and progression of prostate cancer cells. Patients may undergo multiple lines of AR-directed treatments, including androgen-deprivation therapy, AR signaling inhibitors (abiraterone acetate, enzalutamide, apalutamide, or darolutamide), or combinations of these therapies. Yet, tumors inevitably develop resistance to the successive lines of treatment. The diverse mechanisms of resistance include reactivation of the AR and dysregulation of AR cofactors and collaborative transcription factors (TFs). Further elucidating the nexus between the AR and collaborative TFs may reveal new strategies targeting the AR directly or indirectly, such as targeting BET proteins or OCT1. However, appropriate preclinical models will be required to test the efficacy of these approaches. Fortunately, an increasing variety of patient-derived models, such as xenografts and organoids, are being developed for discovery-based research and preclinical drug screening. Here we review the mechanisms of drug resistance in the AR signaling pathway, the intersection with collaborative TFs, and the use of patient-derived models for novel drug discovery.

Original languageEnglish
Article number581515
Number of pages11
JournalFrontiers in Oncology
Volume10
DOIs
Publication statusPublished - 8 Oct 2020

Keywords

  • androgen receptor
  • castration-resistant prostate cancer
  • octamer transcription factor 1
  • preclinical models
  • transcription factors

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