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Abstract
Simple SummaryAndrogen receptor splice variants (AR-Vs) play an important role in prostate cancer progression, especially as a putative resistance mechanism against AR-targeted therapies. Recent technological advances have enabled detection of AR-Vs in many types of human specimens including circulating tumor cells. Here, we discuss the biology of AR-Vs, the clinical utility of AR-Vs as prognostic and predictive biomarkers, and AR-Vs as potential therapeutic targets with a special focus on AR-V7.Over the past decade, advances in prostate cancer research have led to discovery and development of novel biomarkers and effective treatments. As treatment options diversify, it is critical to further develop and use optimal biomarkers for the purpose of maximizing treatment benefit and minimizing unwanted adverse effects. Because most treatments for prostate cancer target androgen receptor (AR) signaling, aberrations affecting this drug target are likely to emerge following the development of castration-resistant prostate cancer (CRPC), and it is conceivable that such aberrations may play a role in drug resistance. Among the many AR aberrations, we and others have been studying androgen receptor splice variants (AR-Vs), especially AR-V7, and have conducted preclinical and clinical studies to develop and validate the clinical utility of AR-V7 as a prognostic and potential predictive biomarker. In this review, we first describe mechanisms of AR-V generation, regulation and their functions from a molecular perspective. We then discuss AR-Vs from a clinical perspective, focusing on the significance of AR-Vs detected in different types of human specimens and AR-Vs as potential therapeutic targets.
Highlights
The androgen receptor (AR) is a member of nuclear receptors activated by androgenic ligands such as testosterone and dihydrotestosterone
Because the development and progression of prostate cancer (PCa) depends on AR signaling, inhibition of AR signaling by androgen deprivation therapy (ADT) is the mainstay of treatment for advanced castration-sensitive PCa (CSPC)
CSPC eventually develops resistance to ADT and progresses to castration-resistant PCa (CRPC), often by gaining an ability to activate AR signaling under low-ligand environments
Summary
The androgen receptor (AR) is a member of nuclear receptors activated by androgenic ligands such as testosterone and dihydrotestosterone. CSPC eventually develops resistance to ADT and progresses to castration-resistant PCa (CRPC), often by gaining an ability to activate AR signaling under low-ligand environments. Even after CRPC develops, ADT is continued indefinitely and combined with secondary hormone therapy agents that further block AR signaling either by suppression of androgen synthesis (e.g., abiraterone) or by direct inhibition of AR (e.g., enzalutamide, apalutamide and darolutamide). Because all these drugs target the AR ligand-binding domain (LBD), truncated AR splice variants (AR-Vs) lacking the LBD, i.e., the drug target, have been evaluated as a biologically plausible mechanism of drug resistance to AR-targeting agents. We will summarize the biology of AR-Vs and their clinical implications with a special focus on AR-V7
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