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    Cell reports. pii: S2211-1247(18)30780-0. doi: 10.1016/j.celrep.2018.05.034
    Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells.
    Sullivan-Reed K1,  Bolton-Gillespie E2,  Dasgupta Y3,  Langer S4,  Siciliano M5,  Nieborowska-Skorska M6,  Hanamshet K7,  Belyaeva EA8,  Bernhardy AJ9,  Lee J10,  Moore M11,  Zhao H12,  Valent P13,  Matlawska-Wasowska K14,  Müschen M15,  Bhatia S16,  Bhatia R17,  Johnson N18,  Wasik MA19,  Mazin AV20,  Skorski T21
    Author information
    1Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
    2Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
    3Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
    4Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
    5Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
    6Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
    7Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
    8Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19102, USA.
    9Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
    10Department of Systems Biology, Beckman Research Institute, Monrovia, CA 91016, USA.
    11Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
    12Department of Clinical Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA.
    13Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig-Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, 1090, Austria.
    14Division of Pediatric Research, Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
    15Department of Systems Biology, Beckman Research Institute, Monrovia, CA 91016, USA.
    16Department of Pediatrics, University of Alabama Birmingham, Birmingham, AL 35223, USA.
    17Division of Hematology-Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35223, USA.
    18Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
    19Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19102, USA.
    20Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
    21Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA. Electronic address: tskorski@temple.edu.
    Abstract

    PARP inhibitors (PARPis) have been used to induce synthetic lethality in BRCA-deficient tumors in clinical trials with limited success. We hypothesized that RAD52-mediated DNA repair remains active in PARPi-treated BRCA-deficient tumor cells and that targeting RAD52 should enhance the synthetic lethal effect of PARPi. We show that RAD52 inhibitors (RAD52is) attenuated single-strand annealing (SSA) and residual homologous recombination (HR) in BRCA-deficient cells. Simultaneous targeting of PARP1 and RAD52 with inhibitors or dominant-negative mutants caused synergistic accumulation of DSBs and eradication of BRCA-deficient but not BRCA-proficient tumor cells. Remarkably, Parp1-/-;Rad52-/- mice are normal and display prolonged latency of BRCA1-deficient leukemia compared with Parp1-/- and Rad52-/- counterparts. Finally, PARPi+RAD52i exerted synergistic activity against BRCA1-deficient tumors in immunodeficient mice with minimal toxicity to normal cells and tissues. In conclusion, our data indicate that addition of RAD52i will improve therapeutic outcome of BRCA-deficient malignancies treated with PARPi.


    Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

    KEYWORDS: BRCA-deficient tumors, PARP1, RAD52, synthetic lethality

    Publikations ID: 29898385
    Quelle: öffnen
     
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