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

doi:10.1016/j.celrep.2017.11.095

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

Research output: Contribution to journal › Article › peer-review

134 Scopus citations

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.

Original language	English
Pages (from-to)	3398-3405
Number of pages	8
Journal	Cell Reports
Volume	21
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2017.11.095
State	Published - Nov 19 2017
Externally published	Yes

Keywords

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
Female
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Nuclear Proteins/metabolism
Ovarian Neoplasms/genetics
Phthalazines/pharmacology
Piperazines/pharmacology
Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
Poly(ADP-ribose) Polymerases/metabolism
Protein-Tyrosine Kinases/metabolism
Proteins/antagonists & inhibitors
Triazoles/pharmacology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2017.11.095

Cite this

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title = "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.",

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author = "Sergey Karakashev and Hengrui Zhu and Yuhki Yokoyama and Bo Zhao and Nail Fatkhutdinov and Kossenkov, {Andrew V} and Wilson, {Andrew J} and Fiona Simpkins and David Speicher and Dineo Khabele and Bitler, {Benjamin G} and Rugang Zhang",

year = "2017",

month = nov,

day = "19",

doi = "10.1016/j.celrep.2017.11.095",

language = "English",

volume = "21",

pages = "3398--3405",

journal = "Cell Reports",

issn = "2211-1247",

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T1 - BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer

AU - Karakashev, Sergey

AU - Zhu, Hengrui

AU - Yokoyama, Yuhki

AU - Zhao, Bo

AU - Fatkhutdinov, Nail

AU - Kossenkov, Andrew V

AU - Wilson, Andrew J

AU - Simpkins, Fiona

AU - Speicher, David

AU - Khabele, Dineo

AU - Bitler, Benjamin G

AU - Zhang, Rugang

PY - 2017/11/19

Y1 - 2017/11/19

N2 - 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.

AB - 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.

KW - Animals

KW - Azepines/pharmacology

KW - BRCA1 Protein/genetics

KW - BRCA2 Protein/genetics

KW - Cell Cycle/drug effects

KW - Cell Cycle Proteins/metabolism

KW - Cell Line, Tumor

KW - DNA Damage

KW - Drug Synergism

KW - Epithelial Cells/drug effects

KW - Female

KW - Humans

KW - Mice

KW - Mice, Inbred NOD

KW - Mice, SCID

KW - Nuclear Proteins/metabolism

KW - Ovarian Neoplasms/genetics

KW - Phthalazines/pharmacology

KW - Piperazines/pharmacology

KW - Poly(ADP-ribose) Polymerase Inhibitors/pharmacology

KW - Poly(ADP-ribose) Polymerases/metabolism

KW - Protein-Tyrosine Kinases/metabolism

KW - Proteins/antagonists & inhibitors

KW - Triazoles/pharmacology

U2 - 10.1016/j.celrep.2017.11.095

DO - 10.1016/j.celrep.2017.11.095

M3 - Article

C2 - 29262321

SN - 2211-1247

VL - 21

SP - 3398

EP - 3405

JO - Cell Reports

JF - Cell Reports

IS - 12

ER -

BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer

Abstract

Keywords

UN SDGs

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