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

TitleCastration-resistant prostate cancer cells are dependent on the high activity of CDK7.
Publication TypeJournal Article
Year of Publication2023
AuthorsPallasaho S, Gondane A, Kuivalainen A, Girmay S, Moestue S, Loda M, Itkonen HM
JournalJ Cancer Res Clin Oncol
Date Published2023 Jul
KeywordsAndrogen Antagonists, Androgens, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinases, Gene Expression Regulation, Neoplastic, Humans, Male, Prostatic Neoplasms, Castration-Resistant, Receptors, Androgen

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.

Alternate JournalJ Cancer Res Clin Oncol
PubMed ID36401094
PubMed Central IDPMC10349716
Grant List331324 / / Academy of Finland /
Related Faculty: 
Massimo Loda, M.D.

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