Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence.

Abstract:

:The androgen receptor (AR) signaling axis drives all stages of prostate cancer, including the lethal, drug-resistant form of the disease termed castration-resistant prostate cancer (CRPC), which arises after failure of androgen deprivation therapy (ADT). Persistent AR activity in spite of ADT and the second-generation AR-targeting agents enzalutamide and abiraterone is achieved in many cases by direct alterations to the AR signaling axis. Herein, we provide a detailed description of how such alterations contribute to the development and progression of CRPC. Aspects of this broad and ever-evolving field specifically addressed in this review include: the etiology and significance of increased AR expression; the frequency and role of gain-of-function mutations in the AR gene; the function of constitutively active, truncated forms of the AR termed AR variants and the clinical relevance of alterations to the activity and expression of AR coregulators. Additionally, we examine the novel therapeutic strategies to inhibit these classes of therapy resistance mechanisms, with an emphasis on emerging agents that act in a manner distinct from the current ligand-centric approaches. Throughout, we discuss how the central role of AR in prostate cancer and the constant evolution of the AR signaling axis during disease progression represent archetypes of two key concepts in oncology, oncogene addiction and therapy-mediated selection pressure.

journal_name

Endocr Relat Cancer

journal_title

Endocrine-related cancer

authors

Coutinho I,Day TK,Tilley WD,Selth LA

doi

10.1530/ERC-16-0422

subject

Has Abstract

pub_date

2016-12-01 00:00:00

pages

T179-T197

issue

12

eissn

1351-0088

issn

1479-6821

pii

ERC-16-0422

journal_volume

23

pub_type

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