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April 1st, 2025
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Department of Obstetrics and Gynaecology, Medical Faculty Mannheim of the Heidelberg University, University Medical Centre Mannheim, 68167 Mannheim, Germany.
cancer biology
biorxiv

Interplay between BET Proteins and the Pre-Replication Complex Unveils Therapeutic Vulnerabilities in Cancer

Doberstein, K.Open in Google Scholar•Messner, V.Open in Google Scholar•Berlit, S.Open in Google Scholar•Tuschy, B.Open in Google Scholar•Suetterlin, M.Open in Google Scholar•Marme, F.Open in Google Scholar

Replication stress is a critical event in cancer development and understanding the underlying molecular mechanisms can help to identify new treatment strategies. Here, we investigate the molecular interplay between the pre-replication complex (pre-RC) and the bromodomain and extraterminal domain (BET) proteins in orchestrating replication stress response. Our findings reveal a mutual dependency between BET proteins and the pre-RC within cancer cells. Notably, reduction in origin licensing or replication initiation makes cells more susceptible to the BET-inhibitor AZD5153. Furthermore, we observe synergistic effects when combining the CDC7 inhibitor XL413 with AZD5153, effects which were partly dependent on TP53 mutation status. This combination treatment results in unresolved DNA damage and R-loop formation, leading to increased genomic instability. These insights pave the way for novel strategies for targeted cancer therapies and provide a foundation for further investigation into the interplay between CDC7 and BET proteins in replication stress response.

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