Figure 1. Blocking androgen signaling in castration-resistant prostate cancer. Nearly all pathways associated with the transition from androgen-dependent to castration-resistant prostate cancer (CRPC) include reactivation of signaling pathways that involve the androgen receptor (AR). In prostate cancer cells, testosterone-bound ARs form dimers that translocate into the nucleus, in which they get recruited to target gene loci on DNA along with an RNA polymerase to initiate the transcription of AR-regulated genes.

At least two targeted therapies are marketed to treat CRPC that can block androgen signaling after first-line androgen ablation therapies are no longer effective. The more upstream-targeted drug is Johnson & Johnson's Zytiga abiraterone acetate (green circle), a small molecule inhibitor of cytochrome P450 17 a-hydroxylase/C17, 20 lyase (CYP17) [a]. The lyase is responsible for converting testosterone precursors such as dehydroepiandrosterone (DHEA) into testosterone, so inhibiting its function decreases the amount of testosterone available to bind to ARs.

The other drug is Medivation Inc.'s Xtandi enzalutamide (blue circle). The drug blocks AR signaling by competing with testosterone for binding to AR [b], which inhibits the translocation of AR into the nucleus [c] and prevents recruitment of nuclear AR to DNA [d].

As reported in Asangani et al., researchers identified a new molecular interaction between AR and BET bromodomain-containing proteins such as BRD2, BRD3 and BRD4. The group found that blocking the AR and BRD2/3/4 interactions with the BET bromodomain inhibitor JQ1 (yellow circle) blocks the co-recruitment of AR and the BET bromodomain-containing proteins to DNA [e]. This results in decreased expression of multiple AR-regulated genes and also inhibits the activity of two known oncogenes: v-ets erythroblastosis virus E26 oncogene homolog (ERG) and c-Myc (MYC).