BRD4 Inhibition Is Synthetic Lethal with PARP Inhibitors through the Induction of Homologous Recombination Deficiency

Chaoyang Sun, Jun Yin, Yong Fang, Jian Chen, Kang Jin Jeong, Xiaohua Chen, Christopher P. Vellano, Zhenlin Ju, Wei Zhao, Dong Zhang, Yiling Lu, Funda Meric-Bernstam, Timothy A. Yap, Maureen Hattersley, Mark J. O'Connor, Huawei Chen, Stephen Fawell, Shiaw Yih Lin, Guang Peng, Gordon Mills

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Poly(ADP-ribose) polymerase inhibitors (PARPi) are selectively active in cells with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1, BRCA2, and other pathway members. We sought small molecules that induce HRD in HR-competent cells to induce synthetic lethality with PARPi and extend the utility of PARPi. We demonstrated that inhibition of bromodomain containing 4 (BRD4) induced HRD and sensitized cells across multiple tumor lineages to PARPi regardless of BRCA1/2, TP53, RAS, or BRAF mutation status through depletion of the DNA double-stand break resection protein CtIP (C-terminal binding protein interacting protein). Importantly, BRD4 inhibitor (BRD4i) treatment reversed multiple mechanisms of resistance to PARPi. Furthermore, PARPi and BRD4i are synergistic in multiple in vivo models. Sun et al. show that inhibition of BRD4 induces homologous recombination deficiency, through depletion of CtBP, in cells across multiple tumor types and sensitizes them to PARP inhibition. Thus, inhibition of BRD4 reverses resistance to PARP inhibitors and expands the potential use of PARP inhibitors.

Original languageEnglish (US)
Pages (from-to)401-416.e8
JournalCancer Cell
Volume33
Issue number3
DOIs
StatePublished - Mar 12 2018
Externally publishedYes

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Keywords

  • BRD4 inhibitor
  • CtBP-interacting protein
  • CtIP
  • homologous recombination
  • PARP inhibitor

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Sun, C., Yin, J., Fang, Y., Chen, J., Jeong, K. J., Chen, X., Vellano, C. P., Ju, Z., Zhao, W., Zhang, D., Lu, Y., Meric-Bernstam, F., Yap, T. A., Hattersley, M., O'Connor, M. J., Chen, H., Fawell, S., Lin, S. Y., Peng, G., & Mills, G. (2018). BRD4 Inhibition Is Synthetic Lethal with PARP Inhibitors through the Induction of Homologous Recombination Deficiency. Cancer Cell, 33(3), 401-416.e8. https://doi.org/10.1016/j.ccell.2018.01.019