CUDC-101, a Novel Inhibitor of Full-Length Androgen Receptor (flAR) and Androgen Receptor Variant 7 (AR-V7) Activity: Mechanism of Action and In Vivo Efficacy

Abstract

Castration resistant prostate cancer (CRPC) is an androgen receptor (AR) dependent disease expected to cause the death of more than 27,000 Americans in 2015. There are only a few available treatments for CRPC, making the discovery of new drugs an urgent need. We report that CUDC-101 (an inhibitor od HER2/NEU, EGFR and HDAC) inhibits both the full length AR (flAR) and the AR variant AR-V7. This observation prompted experiments to discover which of the known activities of CUDC-101 is responsible for the inhibition of flAR/AR-V7 signaling. We used pharmacologic and genetic approaches, and found that the effect of CUDC-101 on flAR and AR-V7 was duplicated only by other HDAC inhibitors, or by silencing the HDAC isoforms HDAC5 and HDAC10. We observed that CUDC-101 treatment or AR-V7 silencing by RNAi equally reduced transcription of the AR-V7 target gene, PSA, without affecting viability of 22Rv1 cells. However, when cellular proliferation was used as an end point, CUDC-101 was more effective than AR-V7 silencing, raising the prospect that CUDC-101 has additional targets beside AR-V7. In support of this, we found that CUDC-101 increased the expression of the cyclin-dependent kinase inhibitor p21, and decreased that of the oncogene HER2/NEU. To determine if CUDC-101 reduces growth in a xenograft model of prostate cancer, this drug was given for 14 days to castrated male SCID mice inoculated with 22Rv1 cells. Compared to vehicle, CUDC-101 reduced xenograft growth in a statistically significant way, and without macroscopic side effects. These studies demonstrate that CUDC-101 inhibits wtAR and AR-V7 activity and growth of 22Rv1 cells in vitro and in vivo. These effects result from the ability of CUDC-101 to target not only HDAC signaling, which was associated with decreased flAR and AR-V7 activity, but multiple additional oncogenic pathways. These observations raise the possibility that treatment of CRPC may be achieved by using similarly multi-targeted approaches.

Droplet Digital PCR Based Androgen Receptor Variant 7 (AR-V7) Detection from Prostate Cancer Patient Blood Biopsies

“…Amongst the PCa cell lines, 22Rv1 showed high AR-V7 levels and AR-V7 versus total AR expression ratios (26%). This agrees with previous studies, using immunoblots to discriminate between full length AR and AR-V7 [ 20 , 21 ]. VCaP, known to carry AR gene amplification [ 22 ], expectedly expressed the highest level of total AR transcript, which was two to seven fold the level of other AR positive cell lines.…”

High‐Content Screening Identifies Src Family Kinases as Potential Regulators of AR‐V7 Expression and Androgen‐Independent Cell Growth

“…Recently, based upon follow‐on data from our original screens described in this report, we published a study that identifies CUDC‐101, an inhibitor of Her2/Neu/EGFR/HDAC, as an effective in vitro and in vivo inhibitor of AR‐V7 transcriptional activity and cell proliferation. This effect of CUDC‐101 was found to be primarily driven by its inhibitory effect on HDAC activity . Our findings and those of others indicate that further study of HDAC inhibitors in patients with AR‐V7–positive CaP may yield promising results.…”

Histone deacetylase 10, a potential epigenetic target for therapy

“…Androgen receptor (AR) is a significant target in treating CRPC, and silencing HDAC10 also reduces the transcriptional activity of androgen receptor (AR)-V7 and full length AR (flAR) in prostate cells (78), which implies that HDAC10 has potential therapeutic value.…”

“…Although the roles of HDAC10 in drug resistance have not been explored completely, experiments suggest that the NCOR2-HDAC10-DUB3-BRD4 signaling pathway might be useful as a regulator of drug resistance in tumors [ 77 ]. AR is a significant target in treating CRPC, and silencing HDAC10 also reduces the transcriptional activity of AR-V7 and full-length AR (flAR) in prostate cells [ 78 ], which implies that HDAC10 has potential therapeutic value.…”