Filling a critical knowledge gap in androgen receptor variant splicing to enable development of new prostate cancer therapies

Abstract

Androgen receptor (AR) signalling has long been recognised as critical in the initiation and progression of prostate cancer (PC). Therapeutic interventions therefore focus on interrupting AR signalling through suppression of circulating testosterone with androgen deprivation therapy (ADT) or direct inhibition of the AR with anti-androgens, such as enzalutamide. Whilst initially effective, a significant proportion of patients will see progression of their disease despite castrate levels of androgens. Castrate-resistant prostate cancer (CRPC) arises through several mechanisms including alternative splicing of the androgen receptor leading to the generation of androgen receptor spliced variants (AR-Vs). Cryptic exons (CEs) of AR-Vs replace the ligand-bind domain (LBD) of the AR consequently rendering them constitutively activated and able to drive disease progression. AR-Vs are currently resistant to all therapeutic interventions and themselves are complex targets due to their high level of structural disorder. Histone demethylase (HDMs) can influence splicing decisions and may offer an alternative therapeutic option to direct targeting of splicing factors (SFs) which often lack specificity to pathophysiological splicing events. KDM6A is one such HDM which is known to be highly mutated in CRPC. However, its role in disease progression is relatively unknown. Data obtained during this PhD reveals that KMD6A contributes to PC progression to CRPC through both catalytic-dependent and independent mechanisms. The influence of KDM6A on splicing appeared to be through the chromatin-adapter model, recruiting SFs to CE3 driving the generation of AR-V7. Critically, this work revealed that in models of enzalutamide resistance, KDM6A inhibition can lead to enzalutamide re-sensitisation by affecting both genes and pathways essential for the emergence of resistance. Results from this work show KDM6A to be an attractive target in CRPC for which there are currently no curative treatment options.