The BET inhibitor INCB054329 reduces homologous recombination efficiency and augments PARP inhibitor activity in ovarian cancer.

Wilson AJ, Stubbs M, Liu P, Ruggeri B, Khabele D
Gynecol Oncol. 2018 149 (3): 575-584

PMID: 29567272 · PMCID: PMC5986599 · DOI:10.1016/j.ygyno.2018.03.049

OBJECTIVE - Homologous recombination (HR)-proficient ovarian tumors have poorer clinical outcomes and show resistance to poly ADP ribose polymerase inhibitors (PARPi). A subset of HR-proficient ovarian tumors show amplification in bromodomain and extra-terminal (BET) genes such as BRD4. We aimed to test the hypothesis that BRD4 inhibition sensitizes ovarian cancer cells to PARPi by reducing HR efficiency and increasing DNA damage.

METHODS - HR-proficient ovarian cancer cell lines (OVCAR-3, OVCAR-4, SKOV-3, UWB1.289+BRCA1) were treated with BRD4-targeting siRNA, novel (INB054329, INCB057643) and established (JQ1) BET inhibitors (BETi) and PARPi (olaparib, rucaparib). Cell growth and viability were assessed by sulforhodamine B assays in vitro, and in SKOV-3 and ovarian cancer patient-derived xenografts in vivo. DNA damage and repair (pH2AX, RAD51 and BRCA1 foci formation, and DRGFP HR reporter activity), apoptosis markers (cleaved PARP, cleaved caspase-3, Bax) and proliferation markers (PCNA, Ki67) were assessed by immunofluorescence and western blot.

RESULTS - In cultured cells, inhibition of BRD4 by siRNA or INCB054329 reduced expression and function of BRCA1 and RAD51, reduced HR reporter activity, and sensitized the cells to olaparib-induced growth inhibition, DNA damage induction and apoptosis. Synergy was observed between all BETi tested and PARPi. INCB054329 and olaparib also co-operatively inhibited xenograft tumor growth, accompanied by reduced BRCA1 expression and proliferation, and increased apoptosis and DNA damage.

CONCLUSIONS - These results provide strong rationale for using BETi to extend therapeutic efficacy of PARPi to HR-proficient ovarian tumors and could benefit a substantial number of women diagnosed with this devastating disease.

Copyright © 2018 Elsevier Inc. All rights reserved.

MeSH Terms (25)

Animals Antineoplastic Combined Chemotherapy Protocols BRCA1 Protein Carcinoma, Ovarian Epithelial Cell Cycle Proteins Cell Line, Tumor Down-Regulation Drug Synergism Female Homologous Recombination Humans Indoles Mice Mice, Inbred NOD Mice, Nude Mice, SCID Neoplasms, Glandular and Epithelial Nuclear Proteins Organic Chemicals Ovarian Neoplasms Phthalazines Piperazines Poly(ADP-ribose) Polymerase Inhibitors Transcription Factors Xenograft Model Antitumor Assays

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