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 language | English (US) |
|---|---|
| Pages (from-to) | 470-479 |
| Number of pages | 10 |
| Journal | European Urology |
| Volume | 67 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2015 |
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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 journal › Article
}
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
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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 -