BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer

  • Cell Rep. 2017 Dec 19;21(12):3398-3405. doi: 10.1016/j.celrep.2017.11.095.
Sergey Karakashev  1 ,  Hengrui Zhu  1 ,  Yuhki Yokoyama  1 ,  Bo Zhao  1 ,  Nail Fatkhutdinov  2 ,  Andrew V Kossenkov  3 ,  Andrew J Wilson  4 ,  Fiona Simpkins  5 ,  David Speicher  6 ,  Dineo Khabele  7 ,  Benjamin G Bitler  1 ,  Rugang Zhang  8
Affiliations
  • 1. Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
  • 2. Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA; Kazan Federal University, Kazan, Russia.
  • 3. Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104, USA.
  • 4. Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.
  • 5. Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Penn Ovarian Cancer Center Research Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 6. Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104, USA; Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
  • 7. Division of Gynecologic Oncology, The University of Kansas School of Medicine, Kansas City, KS 66160, USA.
  • 8. Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: [email protected].
PMID: 29262321 DOI: 10.1016/j.celrep.2017.11.095
Abstract

PARP inhibition is known to be an effective clinical strategy in BRCA mutant cancers, but PARP inhibition has not been applied to BRCA-proficient Tumors. Here, we show the synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers due to mitotic catastrophe. Treatment of BRCA-proficient Ovarian Cancer cells with the BET Inhibitor JQ1 downregulated the G2-M cell-cycle checkpoint regulator Wee1 and the DNA-damage response factor TOPBP1. Combining PARP Inhibitor Olaparib with the BET Inhibitor, we observed a synergistic increase in DNA damage and checkpoint defects, which allowed cells to enter Mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe. Moreover, JQ1 and Olaparib showed synergistic suppression of growth of BRCA-proficient Cancer in vivo in a xenograft Ovarian Cancer mouse model. Our findings indicate that a combination of BET Inhibitor and PARP Inhibitor represents a potential therapeutic strategy for BRCA-proficient cancers.

Keywords
BET inhibitor; PARP inhibitor; epithelial ovarian cancer.