期刊
FRONTIERS IN ONCOLOGY
卷 10, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2020.581515
关键词
androgen receptor; castration-resistant prostate cancer; transcription factors; octamer transcription factor 1; preclinical models
类别
资金
- National Health and Medical Research Council, Australia [GR 1102752, 1138242, 1156570]
- Department of Health and Human Services acting through the Victorian Cancer Agency [MCRF18017]
- EJ Whitten Foundation
- Peter and LyndyWhite Foundation
- P-CREATE from AMED, Japan [JP18ck0106194]
- Takeda Science Foundation
- JSPS KAKENHI [JP19H03793, JP19K09740]
- National Health and Medical Research Council of Australia [1156570, 1138242] Funding Source: NHMRC
The androgen receptor (AR) is the main therapeutic target in advanced prostate cancer, because it regulates the growth and progression of prostate cancer cells. Patients may undergo multiple lines of AR-directed treatments, including androgen-deprivation therapy, AR signaling inhibitors (abiraterone acetate, enzalutamide, apalutamide, or darolutamide), or combinations of these therapies. Yet, tumors inevitably develop resistance to the successive lines of treatment. The diverse mechanisms of resistance include reactivation of the AR and dysregulation of AR cofactors and collaborative transcription factors (TFs). Further elucidating the nexus between the AR and collaborative TFs may reveal new strategies targeting the AR directly or indirectly, such as targeting BET proteins or OCT1. However, appropriate preclinical models will be required to test the efficacy of these approaches. Fortunately, an increasing variety of patient-derived models, such as xenografts and organoids, are being developed for discovery-based research and preclinical drug screening. Here we review the mechanisms of drug resistance in the AR signaling pathway, the intersection with collaborative TFs, and the use of patient-derived models for novel drug discovery.
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