Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer

Watson, Philip A.; Arora, Vivek K.; Sawyers, Charles L.

doi:10.1038/nrc4016

Cited by 1,536Prostate Cancer Treatment and ResearchChromatin Remodeling and CancerProstate Cancer Diagnosis and Treatment

Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer

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Watson, Philip A., Arora, Vivek K., Sawyers, Charles L.·2015·Nature Reviews Cancer

DOI 10.1038/nrc4016PMC PMC4771416

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Abstract

During the past 10 years, preclinical studies implicating sustained androgen receptor (AR) signalling as the primary driver of castration-resistant prostate cancer (CRPC) have led to the development of novel agents targeting the AR pathway that are now in widespread clinical use. These drugs prolong the survival of patients with late-stage prostate cancer but are not curative. In this Review, we highlight emerging mechanisms of acquired resistance to these contemporary therapies, which fall into the three broad categories of restored AR signalling, AR bypass signalling and complete AR independence. This diverse range of resistance mechanisms presents new challenges for long-term disease control, which may be addressable through early use of combination therapies guided by recent insights from genomic landscape studies of CRPC.

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ARi resistance is frequently mediated by upregulation of DNA repair pathways and alternative survival mechanisms.
“ARi resistance is frequently mediated by upregulation of DNA repair pathways and alternative survival mechanisms40.”
From The evolving landscape of antibody-drug conjugates (ADCs) for treatment of prostate cancer (2025) · cites this paper as [40]
The Androgen Receptor Bypass Signaling section describes an alternative resistance mechanism involving upregulation of the glucocorticoid receptor. But Future Therapeutic Options for CRPC describes DNA-repair gene mutations and deficient repair, not upregulation of DNA-repair pathways as a frequent mediator of AR-inhibitor resistance. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Aggressive PCa frequently escapes AR-targeted therapies by reactivating AR signaling.
“However, aggressive PCa frequently escapes these therapies by reactivating AR signaling19.”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [19]

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Authors: Watson, P. A., Arora, V. K., & Sawyers, C. L.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
Washington University in St. Louis (US)
Corresponding author: Watson, Philip A.
Sawyers, Charles L.
ORCID: Watson, Philip A.
Arora, Vivek K.
Sawyers, Charles L.
Venue: Nature Reviews Cancer
Publisher: Springer Science and Business Media LLC
Published: 2015-11-13
Volume: 15
Issue: 12
Pages: 701-711
ISSN: 1474-175X (ISSN-L)
1474-1768
DOI: 10.1038/nrc4016
PMC: PMC4771416
OpenAlex: W2181283187
Cited by: 1,536
References: 148
Citations by year: 2026: 138 · 2025: 188 · 2024: 164 · 2023: 171 · 2022: 168 · 2021: 168 · 2020: 131 · 2019: 131 · 2018: 106 · 2017: 100 · 2016: 66 · 2015: 3
FWCI: 16.26
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature reviews. Cancer (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Howard Hughes Medical Institute (SU2C/AACR)
National Cancer Institute (T32CA160001, R01 CA19387‑01, R01CA155169, P30CA008748, P50CA092629, R01CA193837)
National Institute on Deafness and Other Communication Disorders (R01DC019387)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Diagnosis and Treatment
Keywords: castration-resistant prostate cancer, androgen receptor antagonists, acquired drug resistance, androgen receptor signaling, combination therapy
MeSH terms: Animals, Humans, Male, Prostatic Neoplasms, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, Androgen Receptor Antagonists

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