Abstract 3584: Lysine specific demethylase 1 inhibition attenuates enzalutamide resistant androgen receptor V7 splice variant activation
Authors: Sergio Regufe da Mota, Sarah Bailey, Rosemary A. Strivens, Annette L. Hayden, Graham Packham, Simon J. Crabb
Journal: Cancer Research (2015)

Abstract Prostate cancer remains one of the leading causes of cancer death in men worldwide. The majority of prostate cancer is initially hormone dependent highlighting the central role of the androgen receptor (AR) pathway in this disease. However, in a significant number of the cases, patients relapse and develop castration resistant prostate cancer (CRPC) through a variety of molecular mechanisms, many of which include AR modifications. One common resistant mechanism is through an AR-V7 splice variant lacking the C-terminal ligand-binding domain (LBD) but retaining the transactivating N-terminal domain. AR-V7 is constitutively active. Emerging data imply that hormonal therapy with the AR antagonist enzalutamide, which is highly effective in some CRPC patients, becomes ineffective in the face of AR-V7 consistent with the loss of its LBD binding site. Lysine-specific demethylase 1 (LSD1) is a co-activator of the AR pathway which interacts with the AR to promote androgen-dependent transcription of target genes by ligand-induced demethylation of mono- and dimethylated histone 3 at Lys 9. In this work we identified LSD1 as new potential target for treatment of CRPC resistant to enzalutamide treatment through AR-V7 expression. We used reporter assay experiments in human embryonic kidney 293 cells, deficient for androgen receptor, to investigate the transactivation control of the putative androgen receptor responsive element (ARE) in the presence of the wild type (WT) form and the constitutively active V7 variant of the AR. Using this approach we show that enzalutamide effectively inhibits the activation of the ARE by the AR-WT but not the AR-V7 variant upon stimulation with dihydrotestosterone (DHT). However, treatment with a LSD1 inhibitor shows reduced transcription of the ARE promoter with the AR-wt with DHT stimulation and AR-V7 with and without DHT stimulation. Treatment of an androgen-sensitive human prostate adenocarcinoma cell line (LNCaP) with DHT shows an increase in the expression of prostate specific antigen (PSA) gene, an AR transcriptional target. However when treated with LSD1 inhibitors this activation was impaired or completely blocked as PSA levels were similar to those in non DHT treated sample. Moreover we show that treatment of LNCaP cells with LSD1 inhibitors trigger apoptosis as indicated by PARP cleavage. Together this results show that by targeting LSD1, a co-activator of the AR, we can inhibit the expression of AR target genes in a clinically relevant model of enzalutamide resistant AR-V7 expressing CRPC. LSD1 holds potential as a target for cancer therapy in castration resistant prostate cancer. This work was supported by Prostate Cancer UK. Citation Format: Sergio Regufe da Mota, Sarah Bailey, Rosemary A. Strivens, Annette L. Hayden, Graham Packham, Simon J. Crabb. Lysine specific demethylase 1 inhibition attenuates enzalutamide resistant androgen receptor V7 splice variant activation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3584. doi:10.1158/1538-7445.AM2015-3584