BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer

Publication date: 19 December 2017
Source:Cell Reports, Volume 21, Issue 12
Author(s): 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
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.

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Teaser

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.


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