Targeting a Novel Androgen Receptor-Repressed Pathway in Prostate Cancer Therapy

The primary goal of this study is to investigate the potential roles of protein kinase D (PKD) in mediating therapeutic resistance to ADT and to investigate the impact of PKD small molecule inhibitor (SMI)-based combination therapies to curtail ADT-induced therapy resistance. During the past funding cycle, we examined the cross-regulation of PKD1 by androgen signaling in prostate cancer cells. Our data has identified PKD1 as a novel androgen-repressed gene at transcriptional level. Kinetic analysis indicated that the repression of PKD1 by androgen required the induction of a repressor protein, and AR was required for the suppression of PKD1 by androgen. Downstream of AR, we identified fibroblast growth factor receptor substrate 2 (FRS2) and its downstream MEK/ERK pathway as the mediators of androgen-induced PKD1 repression. Our study indicates that PKD1 is a novel androgen suppressed gene and can be downregulated by androgen through a novel AR/FRS2/MEK/ERK pathway.The upregulation of the prosurvival PKD1 by antiandrogens may contribute to therapeutic resistance in prostate cancer treatment.