With the wide-spread use of abiraterone/enzalutamide for CRPC, there is an urgent need to understand and reverse resistance to these treatments. Studies have implicated glucocorticoid receptor (GR) as activating androgen receptor (AR) signalling and driving resistance. Here we studied progesterone receptor (PR), which is phylogenetically most closely related to the AR. We first used digital droplet PCR in prostate cancer (PCa) cell lines and observed >10 times higher levels of expression in the abiraterone/enzalutamide resistant cell line, LNCaP95 compared to LNCaP, VCaP and 22RV1. We confirmed increased PR expression on western blots. We then proceeded to develop a PR immunohistochemistry assay for studying PCa tissue, including biopsies of bone metastases. We tested 110 biopsies and detected PR-positive cells in 15 (30%) patients including 4 (8%) with >50% of cancer cells PR-positive. ER IHC on an adjacent slide was mutually exclusive. To study the relationship between AR targeting and PR expression, we treated AR-positive PCa cells with AR SiRNA or enzalutamide and observed a 6- and 7- fold rise in PR mRNA respectively, suggesting a close inter-play between these 2 signalling axes. We have developed Tet-On PR-A/PR-B, ER-alpha and GR model for evaluation of induction of treatment resistance.Small molecular PR antagonist, onapristone, inhibited T878A-AR (recently implicated in resistance to abiraterone in 15% of CRPC patients), when co-transferred with an ARE-reporter assay in AR-negative PC3 cells. Our data confirms the presence of PR in a molecular sub-set of PCa. Inhibition of PR with onapristone in combination with abiraterone in abiraterone-resistant CRPC is currently undergoing evaluation in a Phase I/II clinical trial (NCT02049190).
Funding: CRUK, PCUK, Movember Centre of Excellence.
Presenting Author: Karolina Nowakowska, The Institute of Cancer Research, Centre for Evolution and Cancer, Treatment Resistance Team, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK. Email: Karolina.firstname.lastname@example.org