BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer.

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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 21 Issue 12 Pg. 3398-3405 (Dec 19 2017) ISSN: 2211-1247 [Electronic] United States
• PMID: 29262321 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• (+)-JQ1 compound
• Azepines
• BRCA1 Protein
• BRCA2 Protein
• Cell Cycle Proteins
• Nuclear Proteins
• Phthalazines
• Piperazines
• Poly(ADP-ribose) Polymerase Inhibitors
• Proteins
• Triazoles
• bromodomain and extra-terminal domain protein, human
• Poly(ADP-ribose) Polymerases
• Protein-Tyrosine Kinases
• WEE1 protein, human
• olaparib

Topics

• Animals
• Azepines (pharmacology)
• BRCA1 Protein (genetics)
• BRCA2 Protein (genetics)
• Cell Cycle (drug effects)
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• DNA Damage
• Drug Synergism
• Epithelial Cells (drug effects, metabolism)
• Female
• Humans
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Nuclear Proteins (metabolism)
• Ovarian Neoplasms (genetics, metabolism)
• Phthalazines (pharmacology)
• Piperazines (pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Protein-Tyrosine Kinases (metabolism)
• Proteins (antagonists & inhibitors, metabolism)
• Triazoles (pharmacology)