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Inhibition of poly(ADP-ribose) polymerase induces synthetic lethality in BRIP1 deficient ovarian epithelial cells

  • Marcia A. Ciccone
    Correspondence
    Corresponding author at: 2020 Zonal Ave, IRD 520, Los Angeles, CA 90033, USA.
    Affiliations
    USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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  • Crystal L. Adams
    Affiliations
    USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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  • Charles Bowen
    Affiliations
    Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Sciences, MD Anderson Cancer Center, Houston, TX, USA
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  • Teena Thakur
    Affiliations
    Cancer Science Institute of Singapore, National University of Singapore, Singapore
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  • Charité Ricker
    Affiliations
    USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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  • Julie O. Culver
    Affiliations
    USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
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  • Asaf Maoz
    Affiliations
    Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
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  • Marilena Melas
    Affiliations
    The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA
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  • Gregory E. Idos
    Affiliations
    Department of Internal Medicine, Division of Gastroenterology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA
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  • Anand D. Jeyasekharan
    Affiliations
    Cancer Science Institute of Singapore, National University of Singapore, Singapore
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  • Koji Matsuo
    Affiliations
    USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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  • Lynda D. Roman
    Affiliations
    USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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  • Stephen B. Gruber
    Affiliations
    Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, and Beckman Research Institute, Duarte, CA, USA

    Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA
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  • Kevin J. McDonnell
    Affiliations
    Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, and Beckman Research Institute, Duarte, CA, USA

    Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA
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Published:October 05, 2020DOI:https://doi.org/10.1016/j.ygyno.2020.09.040

      Highlights

      • BRIP1 deficiency decreases cell proliferation, impairs homologous recombination, and interferes with DNA repair in vitro.
      • Pathogenic BRIP1 alterations increased susceptibility to platinum agents but not to olaparib monotherapy.
      • The combination of platinum and olaparib therapy resulted in synergistic lethality in cells with expressing altered BRIP1.
      • We provide pre-clinical support for use of PARP-inhibitors in the setting of ovarian cancer patients with BRIP1 mutations.
      • We show pre-clinical evidence for PARP-inhibitor maintenance after platinum treatment in BRIP1-mutated ovarian cancer.

      Abstract

      Objective

      Pathogenic variations in the homologous recombination (HR) gene, BRCA1 interacting protein C-terminal helicase 1 (BRIP1) increase the risk for ovarian cancer. PARP inhibitors (PARPi) exert a synthetic lethal effect in BRCA-mutated ovarian cancers. Effective HR requires cooperation between BRCA1 and BRIP1; therefore, BRIP1-incompetancy may predict vulnerability to synthetic lethality. Here we investigated the response of ovarian epithelial cells with defective BRIP1 function to PARPi, and compared these cells to those lacking BRCA1 activity.

      Methods

      We engineered Chinese Hamster ovarian (CHO) epithelial cells to express deficient BRIP1 or BRCA1, and exposed them to olaparib with or without carboplatin or cisplatin. We assessed cellular proliferation and survival; we calculated inhibitory concentrations and combination and reduction drug indices.

      Results

      BRIP1 and BRCA1 inactivation impedes HR activity, decreases cellular proliferation and compromises DNA damage recovery. Platinum agent exposure impairs cellular survival. Olaparib exposure alone decreases cell viability in BRCA1-deficient cells, although has no effect on BRIP1-deficient cells. Combining carboplatin or cisplatin with olaparib synergistically attenuates cellular survival, consistent with synthetic lethality.

      Conclusions

      BRIP1-deficient ovarian epithelial cells exhibit defective HR, resulting in synthetic lethality when exposed to a platinum agent/PARPi combination. PARPi alone had no effect; this lack of effect may result from distinguishing molecular properties of BRIP1and/or consequences of genomic background. Our study identifies altered BRIP1 as a target for precision medicine-based therapies for ovarian cancers. This investigation supports consideration of the use of a platinum agent/PARPi combination in ovarian cancers depending upon genetic profile and genomic background.

      Keywords

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