Abstract IA18: Altered AR gene architecture and splicing in castration-resistant prostate cancer

Abstract

Abstract Reactivation of the androgen receptor (AR) during androgen depletion therapy (ADT) underlies castration-resistant prostate cancer (CRPCa). Altered splicing of the AR gene and synthesis of constitutively-active COOH-terminally truncated AR variants lacking the AR ligand binding domain has emerged as an important mechanism of ADT-resistance in CRPCa. To understand mechanisms that may promote synthesis of these species, we have been studying the PCa progression models in which altered AR splicing patterns were originally discovered. Remarkably, these models all harbor distinct intragenic rearrangements in the AR gene, which are linked to their individual splicing signatures. For example, the CRPCa 22Rv1 cell line harbors a 35kb intragenic tandem duplication of AR exon 3 and flanking sequences, which results in expression of an exon 3-duplicated full-length AR and multiple truncated AR variant species. The CRPCa LuCaP 86.2 xenograft harbors an 8,579 bp deletion of AR exons 5, 6, and 7, which promotes synthesis of the truncated AR v567es variant. Targeted paired-end re-sequencing of the AR gene in CWR-R1 cells led to the discovery of a 48 kb deletion in AR intron 1, which is linked to a splice switch favoring synthesis of the AR-V7/AR3 variant. Copy number imbalances occur across the length of the AR gene in clinical CRPCa, often concurrent with amplification, indicating complex patterns of intragenic AR gain and loss in human disease. These findings portend ongoing discovery of diverse truncated AR variants in CRPCa and define a new class of AR gene alterations that may drive ADT-resistance at this stage of the disease. Citation Format: Scott M. Dehm. Altered AR gene architecture and splicing in castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA18.