Development of a New Approach for the Therapy of Prostate Cancer with SPOP Mutations

Advanced prostate cancer is treated with androgen deprivation, but most patients eventually progress and need new therapy. Recent genomic/exomic sequencing identified SPOP as the most frequently mutated gene in 6% - 15% of prostate cancer. Based on the function of SPOP as a ubiquitin ligase in protein degradation, it was hypothesized that loss-of-function mutations of SPOP led to accumulation of SPOP substrates that enhance androgen receptor activity and facilitate prostate cancer formation. SPOP substrates could thus be potential targets for treatment of androgen-sensitive prostate cancer. PubMed and BLAST search identified that Gli, SRC-3, and AWP1 are SPOP substrates, and that inhibition of PRK-1, a binding partner of AWP1, by lestaurtinib suppressed androgen receptor activity. LNCaP, PC3, DU145 and 22RV1 prostate cancer cells were used to evaluate the effect of lestaurtinib. LNCaP cells, an androgen-sensitive prostate cancer cell line, were the most sensitive. SRC-3 protein decreased when LNCaP cells were treated with lestaurtinib; whereas PRK-1 increased in nucleus after lestaurtinib treatment. These data suggest that lestaurtinib modulates SRC-3 and PRK-1 to induced cell death in androgen-sensitive prostate cancer, and could be a useful agent for future development for prostate cancer with SPOP mutations.