Sustained reliance on
androgen receptor (AR) after failure of AR-targeting
androgen deprivation
therapy (ADT) prevents effective treatment of
castration-recurrent (CR)
prostate cancer (CaP). Interfering with the molecular machinery by which AR drives CaP progression may be an alternative therapeutic strategy but its feasibility remains to be tested. Here, we explore targeting the mechanism by which AR, via RhoA, conveys
androgen-responsiveness to
serum response factor (SRF), which controls aggressive CaP behavior and is maintained in CR-CaP. Following a
siRNA screen and candidate gene approach,
RNA-Seq studies confirmed that the RhoA effector
Protein Kinase N1 (PKN1) transduces
androgen-responsiveness to SRF.
Androgen treatment induced SRF-PKN1 interaction, and PKN1 knockdown or overexpression severely impaired or stimulated, respectively,
androgen regulation of SRF target genes. PKN1 overexpression occurred during clinical CR-CaP progression, and hastened CaP growth and shortened CR-CaP survival in orthotopic CaP xenografts. PKN1's effects on SRF relied on its
kinase domain. The multikinase inhibitor
lestaurtinib inhibited PKN1 action and preferentially affected
androgen regulation of SRF over direct AR target genes. In a CR-CaP patient-derived xenograft, expression of SRF target genes was maintained while AR target gene expression declined and proliferative gene expression increased. PKN1 inhibition decreased viability of CaP cells before and after ADT. In patient-derived CaP explants,
lestaurtinib increased AR target gene expression but did not significantly alter SRF target gene or proliferative gene expression. These results provide proof-of-principle for selective forms of ADT that preferentially target different fractions of AR's transcriptional output to inhibit CaP growth.