A93: Lysine specific demethylase 1 inhibition attenuates enzalutamide resistant androgen receptor V7 splice variant activation

Sergio Regufe da Mota1,Sarah Bailey1,Rosemary Strivens1,Annette Hayden1,Graham Packham1,Simon Crabb1

1Cancer Research UK Centre, University of Southampton, Southampton, UK

Presenting date: Monday 2 November
Presenting time: 12.20-13.10

Background

In the UK one in eight men will develop prostate cancer at some point during their lives. Despite initial androgen deprivation therapy a significant number of patients with advanced disease will develop castration resistant prostate cancer (CRPC) through a variety of molecular mechanisms. The AR-V7 splice variant, lacking the C-terminal ligand-binding domain (LBD) but retaining a constitutively active N-terminal domain, is a common clinically relevant resistance mechanism. Emerging data implies that the AR antagonist enzalutamide, which is initially highly effective in many CRPC patients, becomes ineffective in the face of AR-V7 consistent with the loss of its LBD binding site.
In this work we identified lysine-specific demethylase 1 (LSD1), a co-activator of the AR pathway, as a potential novel therapeutic target for CRPC resistant to enzalutamide through AR-V7 expression.

Method

We used luciferase response element reporter assay experiments in HEK293 cells, deficient for androgen receptor, to investigate the transactivation control of the putative androgen receptor responsive element (ARE) in the presence of the AR wild type (WT) form or AR-V7. We also performed western blot analysis of human prostate adenocarcinoma cells (LNCaP), expressing AR-WT or AR-V7 following exposure to dihydrotestosterone (DHT) and/or LSD1 chemical inhibition.

Results

AR antagonists effectively inhibited AR-WT including upon stimulation with DHT, but not constitutive activation through the AR-V7 variant. However, LSD1 inhibition attenuated DHT activation of both AR-WT and also AR-V7 constitutive activity. LNCaP AR-V7 expressing cells treated with LSD1 showed decreased PSA levels similar to the non-stimulated AR-WT sample.

Conclusion

LSD1 chemical inhibition depletes AR target gene expression in an enzalutamide resistant AR-V7 model of CRPC. LSD1 holds potential as a target for cancer therapy in castration resistant prostate cancer.