CUDC101 is a new powerful inhibitor of the androgen receptor variant AR-V7

Background

AR reactivation in castration resistant prostate cancer (CRPC) is due to a combination of ligand-dependent (i.e. CPRC acquires the ability to locally synthesize sufficient amount of ligand to activate AR) or -independent [i.e. CRPC accumulates androgen receptor variants (AR-Vs) that lack the carboxy terminus and are constitutively active] mechanisms.  We have observed that the AR variant AR-V7 is highly expressed in bone marrow biopsies of CRPC patients.  It is urgent to identify effective inhibitors of AR-V7, because this molecule is resistant to first (Casodex) and second (Enzalutamide) generation anti-androgens, and CRPC is responsible for the death of 30,000 Americans every year.      

Objective

Our objective is to identify novel effective inhibitors of AR-V7 and to characterize their mechanism of action.

Methods

We have used a microscopy-based screening technology and have isolated a number of inhibitors of AR-V7.  One of the most active is CUDC101, an inhibitor of EGFR, HER2 and HDAC.  The effect of CUDC101 was tested in a PC-3 cell line stably transfected with GFP-AR-V7 and in 22Rv1, a model expressing both full length AR and a number of AR variants which include AR-V7.    

Data

CUDC101 inhibited AR-V7 across cell lines by interfering with the activity of class IIA HDAC’s.  We explored the mechanism of decreased AR-V7 activity and found that the AR-V7 protein is depleted after treatment with CUDC101 and this is due at least in part to decreased stability,.  We wondered if the effect of CUDC101 on AR-V7 could be dissociated form the effects of first and second-generation antiandrogens on full length AR.  Using 22Rv1 cell, we were able to show that CUDC101 but not Casodex or Enzalutamide inhibited genes that are specifically regulated by AR-V7, and suppressed AR-V7-dependent proliferation.

Conclusion

CUDC101 is a powerful inhibitor of AR-V7.  By inhibiting AR-V7, CUDC101 decreases cell proliferation and blocks the expression of AR-V7 dependent transcripts.  CUDC101 will be next used in models of CRPC xenografts.