Journal article
Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells
Cell reports (Cambridge), v 23(11), pp 3127-3136
12 Jun 2018
PMID: 29898385
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
[Display omitted]
•RAD52 inhibitors attenuate SSA and residual HR in BRCA-deficient cells•PARP + RAD52 inhibitors exert dual synthetic lethality in BRCA-deficient cells•RAD52 inhibitor improves the effect of PARP inhibitor in BRCA-deficient tumors
Sullivan-Reed et al. show that simultaneous treatment with PARP and RAD52 inhibitors exerts dual synthetic lethality in BRCA-deficient tumors. Addition of RAD52 inhibitor should improve therapeutic outcome of BRCA-deficient malignancies treated with PARP inhibitor.
Metrics
Details
- Title
- Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells
- Creators
- Katherine Sullivan-Reed - Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USAElisabeth Bolton-Gillespie - Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USAYashodhara Dasgupta - Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USASamantha Langer - Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USAMicheal Siciliano - Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USAMargaret Nieborowska-Skorska - Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USAKritika Hanamshet - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USAElizaveta A Belyaeva - Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19102, USAAndrea J Bernhardy - Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USAJaewong Lee - Department of Systems Biology, Beckman Research Institute, Monrovia, CA 91016, USAMorgan Moore - Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USAHuaqing Zhao - Department of Clinical Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USAPeter Valent - Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig-Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, 1090, AustriaKsenia Matlawska-Wasowska - Division of Pediatric Research, Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USAMarkus Müschen - Department of Systems Biology, Beckman Research Institute, Monrovia, CA 91016, USASmita Bhatia - Department of Pediatrics, University of Alabama Birmingham, Birmingham, AL 35223, USARavi Bhatia - Division of Hematology-Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35223, USANeil Johnson - Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USAMariusz A Wasik - Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19102, USAAlexander V Mazin - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USATomasz Skorski - Department of Microbiology and Immunology and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Publication Details
- Cell reports (Cambridge), v 23(11), pp 3127-3136
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000435196500001
- Scopus ID
- 2-s2.0-85047981874
- Other Identifier
- 991014877661604721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cell Biology