Androgen receptor (AR) plays a critical role in the progression of both androgen-dependent and androgen-independent prostate cancer (AIPC). Ligand-independent activation of AR in AIPC or castration resistant prostate cancer (CRPC) is often associated with poor prognosis. We have demonstrated that tyrosine kinase Ack1 regulates AR activity by directly phosphorylating it at tyrosine 267, an event that had not been reported earlier in literature. We have uncovered that Tyr267-phosphorylation of AR was critical for AIPC growth. Prostate tissue microarray analysis indicates that Ack1 Tyr284 phosphorylation correlates positively with disease progression and negatively with the survival of prostate cancer patients.
It is critical in the field of prostate cancer to identify a small molecule inhibitor that is capable of inhibiting AR tyrosine phosphorylation and transcriptional activation. To address this issue, we have generated two key resources,
We observed that neither pTyr267-AR expression nor its transcriptional activation was affected by anti-androgens in activated Ack1 expressing prostate cells. However, the Ack1 inhibitor, AIM-100, not only inhibited Ack1 activation but was also able to suppress pTyr267-AR phosphorylation, binding of AR to PSA, NKX3.1, and TMPRSS2 promoters, and inhibit AR transcription activity. Thus, Ack1 Tyr284 phosphorylation is prognostic of progression of prostate cancer and inhibitors of Ack1 activity could be novel therapeutic agents to treat AIPC.