Abstract IA21: Transcriptional programs directed by the androgen receptor splice variants

Continued androgen receptor (AR) signaling is an established mechanism underlying castration-resistant prostate cancer (CRPC), and suppression of AR signaling remains a therapeutic goal of CRPC therapy. Constitutively active androgen receptor splice variants (AR-Vs) lack the AR ligand-binding domain (AR-LBD), the intended target of androgen deprivation therapies (ADT) including new CRPC therapies such as abiraterone and MDV3100. Transcriptional programs directed by the canonical full-length AR (AR-FL) are well characterized, but those directed the AR-Vs are not well understood. In addition, AR-FL and AR-Vs are both increased in CRPC, underscoring the critical importance of dissecting the complex interplay between AR-FL and AR-Vs. In this study, we employed a set of detection and targeting tools that differentiate the AR-FL and AR-Vs to investigate the functional distinctions between AR-FL and AR-V. We show that suppression of endogenous AR-FL signaling by targeting AR-LBD leads to increased AR-V expression in two cell line models of CRPC. Importantly, treatment-induced AR-Vs activate a distinct expression signature enriched for cell cycle genes without requiring the presence of AR-FL. Conversely, activation of AR-FL signaling suppresses the AR-V-mediated transcriptional programs but activates genes mainly associated with macromolecular synthesis, metabolism, and differentiation. In prostate cancer cells and CRPC xenografts treated with MDV3100 and abiraterone, increased expression of two constitutively active AR-Vs, AR-V7 and ARV567ES, but not AR-FL, parallels increased expression of the AR-driven cell cycle gene UBE2C. In addition, protein expression of AR-V7, but not AR-FL, is positively correlated with UBE2C in clinical CRPC specimens. The cumulative in vitro and in vivo evidence support an adaptive shift toward AR-V-mediated signaling in at least a subset of CRPC tumors as the AR-LBD is rendered inactive, suggesting a functional dichotomy between AR-FL and AR-Vs in a therapeutic setting. The dynamic interplay between AR signaling mediated by AR-FL and AR-V should be further explored in rational development of novel CRPC therapies and multipurpose biomarkers for CRPC. Citation Format: Rong Hu, Changxue Lu, Elahe A. Mostaghel, Srinivasan Yegnasubramanian, Meltem Gurel, Clare Tannahill, Joanne Edwards, William Isaacs, Peter S. Nelson, Eric Bluemn, Stephen R. Plymate, Jun Luo. Transcriptional programs directed by the androgen receptor splice variants [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 IA21.