Castration-resistant prostate cancer cells are dependent on the high activity of CDK7.

Overview

abstract

PURPOSE: Prostate cancer (PC) is successfully treated with anti-androgens; however, a significant proportion of patients develop resistance against this therapy. Anti-androgen-resistant disease (castration-resistant prostate cancer; CRPC) is currently incurable. Cyclin-dependent kinase 7 (CDK7) is positioned to positively regulate both cell cycle and transcription, the two features critical for the rapid proliferation of the CRPC cells. Here, we assess if CDK7 is a viable target to halt the proliferation of CRPC cells. METHODS: We use recently developed clinically relevant compounds targeting CDK7 and multiple cell proliferation assays to probe the importance of this kinase for the proliferation of normal, androgen-dependent, and CRPC cells. PC patient data were used to evaluate expression of CDK7 at different disease-stages. Finally, comprehensive glycoproteome-profiling was performed to evaluate CDK7 inhibitor effects on androgen-dependent and CRPC cells. RESULTS: We show that CDK7 is overexpressed in PC patients with poor prognosis, and that CRPC cells are highly sensitive to compounds targeting CDK7. Inhibition of O-GlcNAc transferase sensitizes the CRPC, but not androgen-dependent PC cells, to CDK7 inhibitors. Glycoproteome-profiling revealed that CDK7 inhibition induces hyper-O-GlcNAcylation of the positive transcription elongation complex (pTEFB: CDK9 and CCNT1) in the CRPC cells. Accordingly, co-targeting of CDK7 and CDK9 synergistically blocks the proliferation of the CRPC cells but does not have anti-proliferative effects in the normal prostate cells. CONCLUSION: We show that CRPC cells, but not normal prostate cells, are addicted on the high activity of the key transcriptional kinases, CDK7 and CDK9.