AR Splicing Variants and Resistance to AR Targeting Agents

Abstract

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.

Choice of antibody is critical for specific and sensitive detection of androgen receptor splice variant-7 in circulating tumor cells

“…Firstly, we conducted protein Blast searches (blast.ncbi.nlm.nih.gov/Blast.cgi?PAGE = Proteins) of the full AR-V7 speci c 16 amino acid sequence as well as the sequence from amino acid 580 and 600 (see Fig. 1A) to the C-terminus of AR-V7 against the human protein database (https://www.uniprot.org), which identi ed only the AR-V7 splice variant and for the 580/600 to C-terminus peptide additionally to AR-V7 the partially homologue AR variant 5 (see ref [23] for review of AR variants). Additionally, we were able to elute the ~ 62kDa PC3 AR−/AR−V7− band of interest from a gel to perform mass spectroscopy and the retrieved data con rmed our Blast data with no proteins detected that share homology to AR-V7 or AR-FL in the excised protein band of interest from PC3 AR−/AR−V7− cells.…”

The promising role of new molecular biomarkers in prostate cancer: from coding and non-coding genes to artificial intelligence approaches

“…Similarly, other proteins related to splicing process, such as KDM4B [ 28 ], CDK9 [ 29 ] and SF3B2 [ 30 ] have been recently associated with generation of androgen receptor variant AR-V7 ( p -value < 0.05 [ 28 – 30 ]). Furthermore, the splicing variants by themselves are of particular interest for PCa research [ 31 ], androgen receptor variants [ 32 ] have been described as important factors in PCa development and prognosis, such as variant AR-V3 and its prognostic value ( p -value = 0.05) [ 33 ]. Likewise, HRAS [ 34 ] and PRUNE2 [ 35 ] are novel variants related to PCa development with clinical utility yet to be confirmed.…”

Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective

“…The full-length AR protein has four distinct domains, N-terminal (NTD), DNA-binding (DBD), hinge region, and C-terminal ligand-binding (LBD). In prostate cancers, the transcriptional splicing variants of the AR gene have been linked to castrationresistance of prostate cancer after ADT and anti-AR therapy with Enzalutamide and Abiraterone (110)(111)(112). Because these AR variant proteins lack the AR C-terminal LBD region due to gene splicing truncated or deleted, they are not responding to current anti-AR drugs that target the LBD.…”