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

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

  • J Cancer Res Clin Oncol. 2022 Nov 18. doi: 10.1007/s00432-022-04475-3.
Satu Pallasaho 1 Aishwarya Gondane 1 Anni Kuivalainen 1 Samuel Girmay 1 Siver Moestue 2 3 Massimo Loda 4 5 6 Harri M Itkonen 7 8
Affiliations

Affiliations

  • 1 Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, PL 63 (Haartmaninkatu 8), 00014, Helsinki, Finland.
  • 2 Department of Clinical and Molecular Medicine, NTNU, Trondheim, Norway.
  • 3 Department of Pharmacy, Nord University, Namsos, Bodø, Norway.
  • 4 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY, USA.
  • 5 The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 6 The New York Genome Center, New York, NY, USA.
  • 7 Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, PL 63 (Haartmaninkatu 8), 00014, Helsinki, Finland. [email protected].
  • 8 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY, USA. [email protected].
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.

Keywords

Castration-resistant prostate cancer; Cyclin-dependent kinase 7; Cyclin-dependent kinase 9; O-GlcNAc transferase.

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