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.

Keywords: AR-V7; androgen receptor splice variants; castration-resistant prostate cancer; circulating tumor cells.

Figure 1

Summary of AR-V structures. (A) The structure and locations of AR gene exon and cryptic exon (CE) junctions are depicted according to GRCh38/hg38 (not drawn to scale). Non-shaded boxes represent canonical exons and shaded boxes represent exon 1b and CEs. Coordinates corresponding to the canonical exon junctions are labeled with red numbers, whereas black numbers mark the coordinates for exon 1b and CEs as well as locations of other variant-specific sequences in some AR-Vs (AR-23, AR8, AR-V6, 8, 10) shown as color-coded boxes. AR-23 and AR8 contain a 69-nucleotide insertion (blue) immediately upstream of the 5′ junction for Exon 3. AR-V6 has an 80-nucleotide insertion (purple) upstream of 5′ end of CE2. A pink box (3′ end of AR-V8) is a part of CE1 at 3′ end of CE1. A green box (3′ end of AR-V10) is located in the middle of CE3. A yellow box in exon 8 was originally named exon 9. AR-45 and AR8 start from 602 nucleotides downstream of Exon 1 (a blue line). The 3′ end of CE1 shown in this figure is approximately 550 nucleotides downstream of the sequence reported in NCBI database. (B) AR-Vs are classified according to their transcriptional activity. Alternative names are shown in brackets. Purple arrowheads indicate locations of a start codon. All AR-Vs, excluding AR-45, have the same start codon as AR-FL; thus, purple arrowheads are omitted from the figure. Black arrowheads indicate the locations of stop codons. AR-V10 has a 7-nucleotide truncation at 3′ end and it is indicated as 3*. A portion of exon 8, indicated as 8* in AR-V13 and 14, was originally called exon 9. Proteins are shown on the right. Amino acids, in bold black font, originate from canonical exons and those in grey are variant-specific peptide sequences.