Targeting Androgen Receptor-Bypass Mechanisms to Enhance Prostate Cancer Therapy

DNPC prostate cancers that evolve as a direct result of increased selective pressures to bypass AR signaling are of increasing importance and likely represent the next major challenge for the treatment of prostate cancer. Autocrine and paracrine FGF pathway activation can bypass AR dependence and targeting the FGF and MAPK pathways can repress AR-null prostate cancer. We further found that TP53 and RB1 play a role in uncoupling the prostate cancer cell from control of androgen through dysregulation of cell cycle. However, dual loss of TP53 and RB1 is insufficient to mediate a full transition to DNPC. Finally, we identified an additional therapeutic approach to DNPC thought targeting DNMT though the inhibitor SGI1027.