TY - JOUR
T1 - Androgen receptor signaling in castration-resistant prostate cancer
T2 - A lesson in persistence
AU - Coutinho, Isabel
AU - Day, Tanya K.
AU - Tilley, Wayne D.
AU - Selth, Luke A.
PY - 2016/12
Y1 - 2016/12
N2 - 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.
AB - 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.
KW - Androgen receptor
KW - Endocrine therapy resistance
KW - Hormone structure/function
KW - Prostate
UR - http://www.scopus.com/inward/record.url?scp=84997719771&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/1083961
UR - http://purl.org/au-research/grants/NHMRC/1008349
U2 - 10.1530/ERC-16-0422
DO - 10.1530/ERC-16-0422
M3 - Review article
C2 - 27799360
AN - SCOPUS:84997719771
SN - 1351-0088
VL - 23
SP - T179-T197
JO - Endocrine-Related Cancer
JF - Endocrine-Related Cancer
IS - 12
ER -