BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer
Sergey Karakashev,
Hengrui Zhu,
Yuhki Yokoyama,
Bo Zhao,
Nail Fatkhutdinov,
Andrew V. Kossenkov,
Andrew J. Wilson,
Fiona Simpkins,
David Speicher,
Dineo Khabele,
Benjamin G. Bitler,
Rugang Zhang
Affiliations
Sergey Karakashev
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA
Hengrui Zhu
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA
Yuhki Yokoyama
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA
Bo Zhao
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA
Nail Fatkhutdinov
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA; Kazan Federal University, Kazan, Russia
Andrew V. Kossenkov
Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104, USA
Andrew J. Wilson
Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA
Fiona Simpkins
Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Penn Ovarian Cancer Center Research Center, University of Pennsylvania, Philadelphia, PA 19104, USA
David Speicher
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
Dineo Khabele
Division of Gynecologic Oncology, The University of Kansas School of Medicine, Kansas City, KS 66160, USA
Benjamin G. Bitler
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA
Rugang Zhang
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA; Corresponding author
Summary: 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. : Karakashev et al. show synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers. This combination of inhibitors can synergistically increase DNA damage and cell-cycle checkpoint defects, which allows cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe. Keywords: epithelial ovarian cancer, BET inhibitor, PARP inhibitor
