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BRD4 facilitates replication stress-induced DNA damage response

Oncogene volume 37, pages 3763–3777 (2018)Cite this article

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Abstract

Previous reports have demonstrated that select cancers depend on BRD4 to regulate oncogenic gene transcriptional programs. Here we describe a novel role for BRD4 in DNA damage response (DDR). BRD4 associates with and regulates the function of pre-replication factor CDC6 and plays an indispensable part in DNA replication checkpoint signaling. Inhibition of BRD4 by JQ1 or AZD5153 resulted in a rapid, time-dependent reduction in CHK1 phosphorylation and aberrant DNA replication re-initiation. Furthermore, BRD4 inhibition sensitized cancer cells to various replication stress-inducing agents, and synergized with ATR inhibitor AZD6738 to induce cell killing across a number of cancer cell lines. The synergistic interaction between AZD5153 and AZD6738 is translatable to in vivo ovarian cell-line and patient-derived xenograft models. Taken together, our study uncovers a new biological function of BRD4 and provides mechanistic rationale for combining BET inhibitors with DDR-targeted agents for cancer therapy.

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Acknowledgements

We thank the W.M. Keck Biotechnology Resource Laboratory at Yale University School of Medicine for their mass spectrometry and proteomics service and technical support, Champions Oncology for performing patient-derived xenograft model screening, Eric Tang from AstraZeneca cell screening team for generating cell panel combination data, and Laura Prickett from Oncology Bioscience team for assistance with flow cytometry analysis. We would also like to thank team members of the AstraZeneca IMED Oncology DNA Damage Response Biology Area for critical reading of the manuscript and their expertize and suggestions.

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  1. These authors contributed equally: Jingwen Zhang and Austin M. Dulak.

Authors and Affiliations

  1. Oncology, IMED Biotech Unit, AstraZeneca R&D, Boston, USA

    Jingwen Zhang, Austin M. Dulak, Maureen M. Hattersley, Brandon S. Willis, Corinne Reimer, Michael Zinda, Stephen E. Fawell & Huawei Chen

  2. Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK

    Jenni Nikkilä, Anderson Wang & Alan Lau

  3. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Gordon B. Mills

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Correspondence to Huawei Chen.

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JZ, AMD, MHH, BSW, JN, AW, AL, CR, MZ, SEF, and HC are employees of AstraZeneca Pharmaceuticals LP, and GBM chairs the Scientific Advisory Board of IMED Oncology and receives sponsored research support from AstraZeneca.

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Zhang, J., Dulak, A.M., Hattersley, M.M. et al. BRD4 facilitates replication stress-induced DNA damage response. Oncogene 37, 3763–3777 (2018). https://doi.org/10.1038/s41388-018-0194-3

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