Understanding the mechanisms of androgen deprivation resistance in prostate cancer at the molecular level

Theodoros Karantanos, Christopher P Evans, Bertrand Tombal, Timothy C. Thompson, Rodolfo Montironi, William B. Isaacs

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

Context Various molecular mechanisms play a role in the development of resistance to androgen deprivation therapy in castration-resistant prostate cancer (CRPC). Objective To understand the mechanisms and biological pathways associated with the progression of prostate cancer (PCa) under systemic androgen depletion or administration of the novel antiandrogens abiraterone, enzalutamide, and ARN-509. This review also examines the introduction of novel combinational approaches for patients with CRPC. Evidence acquisition PubMed was the data source. Keywords for the search were castrate resistant prostate cancer, abiraterone, enzalutamide resistance mechanisms, resistance to androgen deprivation, AR mutations, amplifications, splice variants, and AR alterations. Papers published before 1990 were excluded from the review, and only English-language papers were included. Evidence synthesis This review summarizes the current literature regarding the mechanisms implicated in the development of CRPC and the acquisition of resistance to novel antiandrogen axis agents. The review focuses on androgen biosynthesis in the tumor microenvironment, androgen receptor (AR) alterations and post-transcriptional modifications, the role of glucocorticoid receptor, and alternative oncogenic signaling that is derepressed on maximum AR inhibition and thus promotes cancer survival and progression. Conclusions The mechanisms implicated in the development of resistance to AR inhibition in PCa are multiple and complex, involving virtually all classes of genomic alteration and leading to a host of selective/adaptive responses. Combinational therapeutic approaches targeting both AR signaling and alternative oncogenic pathways may be reasonable for patients with CRPC. Patient summary We looked for mechanisms related to the progression of PCa in patients undergoing hormonal therapy and treatment with novel drugs targeting the AR. Based on recent data, combining maximal AR inhibition with novel agents targeting other tumor-compensatory, non-AR-related pathways may improve the survival and quality of life of patients with castration-resistant PCa.

Original languageEnglish (US)
Pages (from-to)470-479
Number of pages10
JournalEuropean Urology
Volume67
Issue number3
DOIs
StatePublished - Mar 1 2015

Fingerprint

Androgen Receptors
Androgens
Prostatic Neoplasms
Castration
Androgen Antagonists
Tumor Microenvironment
Survival
Information Storage and Retrieval
Glucocorticoid Receptors
Therapeutics
Drug Delivery Systems
PubMed
Neoplasms
Language
Quality of Life
Mutation
Inhibition (Psychology)

Keywords

  • Alternative signaling
  • Androgen receptor
  • Castration-resistant prostate cancer
  • Novel antiandrogens

ASJC Scopus subject areas

  • Urology

Cite this

Understanding the mechanisms of androgen deprivation resistance in prostate cancer at the molecular level. / Karantanos, Theodoros; Evans, Christopher P; Tombal, Bertrand; Thompson, Timothy C.; Montironi, Rodolfo; Isaacs, William B.

In: European Urology, Vol. 67, No. 3, 01.03.2015, p. 470-479.

Research output: Contribution to journalArticle

Karantanos, Theodoros ; Evans, Christopher P ; Tombal, Bertrand ; Thompson, Timothy C. ; Montironi, Rodolfo ; Isaacs, William B. / Understanding the mechanisms of androgen deprivation resistance in prostate cancer at the molecular level. In: European Urology. 2015 ; Vol. 67, No. 3. pp. 470-479.
@article{505652d63bbc4f5ca7f8b28de81e9f41,
title = "Understanding the mechanisms of androgen deprivation resistance in prostate cancer at the molecular level",
abstract = "Context Various molecular mechanisms play a role in the development of resistance to androgen deprivation therapy in castration-resistant prostate cancer (CRPC). Objective To understand the mechanisms and biological pathways associated with the progression of prostate cancer (PCa) under systemic androgen depletion or administration of the novel antiandrogens abiraterone, enzalutamide, and ARN-509. This review also examines the introduction of novel combinational approaches for patients with CRPC. Evidence acquisition PubMed was the data source. Keywords for the search were castrate resistant prostate cancer, abiraterone, enzalutamide resistance mechanisms, resistance to androgen deprivation, AR mutations, amplifications, splice variants, and AR alterations. Papers published before 1990 were excluded from the review, and only English-language papers were included. Evidence synthesis This review summarizes the current literature regarding the mechanisms implicated in the development of CRPC and the acquisition of resistance to novel antiandrogen axis agents. The review focuses on androgen biosynthesis in the tumor microenvironment, androgen receptor (AR) alterations and post-transcriptional modifications, the role of glucocorticoid receptor, and alternative oncogenic signaling that is derepressed on maximum AR inhibition and thus promotes cancer survival and progression. Conclusions The mechanisms implicated in the development of resistance to AR inhibition in PCa are multiple and complex, involving virtually all classes of genomic alteration and leading to a host of selective/adaptive responses. Combinational therapeutic approaches targeting both AR signaling and alternative oncogenic pathways may be reasonable for patients with CRPC. Patient summary We looked for mechanisms related to the progression of PCa in patients undergoing hormonal therapy and treatment with novel drugs targeting the AR. Based on recent data, combining maximal AR inhibition with novel agents targeting other tumor-compensatory, non-AR-related pathways may improve the survival and quality of life of patients with castration-resistant PCa.",
keywords = "Alternative signaling, Androgen receptor, Castration-resistant prostate cancer, Novel antiandrogens",
author = "Theodoros Karantanos and Evans, {Christopher P} and Bertrand Tombal and Thompson, {Timothy C.} and Rodolfo Montironi and Isaacs, {William B.}",
year = "2015",
month = "3",
day = "1",
doi = "10.1016/j.eururo.2014.09.049",
language = "English (US)",
volume = "67",
pages = "470--479",
journal = "European Urology",
issn = "0302-2838",
publisher = "Elsevier",
number = "3",

}

TY - JOUR

T1 - Understanding the mechanisms of androgen deprivation resistance in prostate cancer at the molecular level

AU - Karantanos, Theodoros

AU - Evans, Christopher P

AU - Tombal, Bertrand

AU - Thompson, Timothy C.

AU - Montironi, Rodolfo

AU - Isaacs, William B.

PY - 2015/3/1

Y1 - 2015/3/1

N2 - Context Various molecular mechanisms play a role in the development of resistance to androgen deprivation therapy in castration-resistant prostate cancer (CRPC). Objective To understand the mechanisms and biological pathways associated with the progression of prostate cancer (PCa) under systemic androgen depletion or administration of the novel antiandrogens abiraterone, enzalutamide, and ARN-509. This review also examines the introduction of novel combinational approaches for patients with CRPC. Evidence acquisition PubMed was the data source. Keywords for the search were castrate resistant prostate cancer, abiraterone, enzalutamide resistance mechanisms, resistance to androgen deprivation, AR mutations, amplifications, splice variants, and AR alterations. Papers published before 1990 were excluded from the review, and only English-language papers were included. Evidence synthesis This review summarizes the current literature regarding the mechanisms implicated in the development of CRPC and the acquisition of resistance to novel antiandrogen axis agents. The review focuses on androgen biosynthesis in the tumor microenvironment, androgen receptor (AR) alterations and post-transcriptional modifications, the role of glucocorticoid receptor, and alternative oncogenic signaling that is derepressed on maximum AR inhibition and thus promotes cancer survival and progression. Conclusions The mechanisms implicated in the development of resistance to AR inhibition in PCa are multiple and complex, involving virtually all classes of genomic alteration and leading to a host of selective/adaptive responses. Combinational therapeutic approaches targeting both AR signaling and alternative oncogenic pathways may be reasonable for patients with CRPC. Patient summary We looked for mechanisms related to the progression of PCa in patients undergoing hormonal therapy and treatment with novel drugs targeting the AR. Based on recent data, combining maximal AR inhibition with novel agents targeting other tumor-compensatory, non-AR-related pathways may improve the survival and quality of life of patients with castration-resistant PCa.

AB - Context Various molecular mechanisms play a role in the development of resistance to androgen deprivation therapy in castration-resistant prostate cancer (CRPC). Objective To understand the mechanisms and biological pathways associated with the progression of prostate cancer (PCa) under systemic androgen depletion or administration of the novel antiandrogens abiraterone, enzalutamide, and ARN-509. This review also examines the introduction of novel combinational approaches for patients with CRPC. Evidence acquisition PubMed was the data source. Keywords for the search were castrate resistant prostate cancer, abiraterone, enzalutamide resistance mechanisms, resistance to androgen deprivation, AR mutations, amplifications, splice variants, and AR alterations. Papers published before 1990 were excluded from the review, and only English-language papers were included. Evidence synthesis This review summarizes the current literature regarding the mechanisms implicated in the development of CRPC and the acquisition of resistance to novel antiandrogen axis agents. The review focuses on androgen biosynthesis in the tumor microenvironment, androgen receptor (AR) alterations and post-transcriptional modifications, the role of glucocorticoid receptor, and alternative oncogenic signaling that is derepressed on maximum AR inhibition and thus promotes cancer survival and progression. Conclusions The mechanisms implicated in the development of resistance to AR inhibition in PCa are multiple and complex, involving virtually all classes of genomic alteration and leading to a host of selective/adaptive responses. Combinational therapeutic approaches targeting both AR signaling and alternative oncogenic pathways may be reasonable for patients with CRPC. Patient summary We looked for mechanisms related to the progression of PCa in patients undergoing hormonal therapy and treatment with novel drugs targeting the AR. Based on recent data, combining maximal AR inhibition with novel agents targeting other tumor-compensatory, non-AR-related pathways may improve the survival and quality of life of patients with castration-resistant PCa.

KW - Alternative signaling

KW - Androgen receptor

KW - Castration-resistant prostate cancer

KW - Novel antiandrogens

UR - http://www.scopus.com/inward/record.url?scp=84922121997&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84922121997&partnerID=8YFLogxK

U2 - 10.1016/j.eururo.2014.09.049

DO - 10.1016/j.eururo.2014.09.049

M3 - Article

C2 - 25306226

AN - SCOPUS:84922121997

VL - 67

SP - 470

EP - 479

JO - European Urology

JF - European Urology

SN - 0302-2838

IS - 3

ER -