Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells

  • Cell Rep. 2018 Jun 12;23(11):3127-3136. doi: 10.1016/j.celrep.2018.05.034.
Katherine Sullivan-Reed  1 ,  Elisabeth Bolton-Gillespie  1 ,  Yashodhara Dasgupta  1 ,  Samantha Langer  1 ,  Micheal Siciliano  1 ,  Margaret Nieborowska-Skorska  1 ,  Kritika Hanamshet  2 ,  Elizaveta A Belyaeva  3 ,  Andrea J Bernhardy  4 ,  Jaewong Lee  5 ,  Morgan Moore  1 ,  Huaqing Zhao  6 ,  Peter Valent  7 ,  Ksenia Matlawska-Wasowska  8 ,  Markus Müschen  5 ,  Smita Bhatia  9 ,  Ravi Bhatia  10 ,  Neil Johnson  4 ,  Mariusz A Wasik  3 ,  Alexander V Mazin  2 ,  Tomasz Skorski  11
Affiliations
  • 1. 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.
  • 2. Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
  • 3. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19102, USA.
  • 4. Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
  • 5. Department of Systems Biology, Beckman Research Institute, Monrovia, CA 91016, USA.
  • 6. Department of Clinical Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA.
  • 7. Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig-Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, 1090, Austria.
  • 8. Division of Pediatric Research, Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
  • 9. Department of Pediatrics, University of Alabama Birmingham, Birmingham, AL 35223, USA.
  • 10. Division of Hematology-Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35223, USA.
  • 11. 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. Electronic address: [email protected].
PMID: 29898385 DOI: 10.1016/j.celrep.2018.05.034
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.

Keywords
BRCA-deficient tumors; PARP1; RAD52; synthetic lethality.
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