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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BRCA1 Protein / deficiency
  • BRCA1 Protein / genetics*
  • BRCA2 Protein / deficiency
  • BRCA2 Protein / genetics*
  • DNA Repair / drug effects
  • Female
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism
  • Homologous Recombination / drug effects
  • Humans
  • Imatinib Mesylate / pharmacology
  • Kaplan-Meier Estimate
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / mortality
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Phthalazines / pharmacology
  • Piperazines / pharmacology
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
  • Poly (ADP-Ribose) Polymerase-1 / deficiency
  • Poly (ADP-Ribose) Polymerase-1 / genetics*
  • Rad52 DNA Repair and Recombination Protein / antagonists & inhibitors
  • Rad52 DNA Repair and Recombination Protein / deficiency
  • Rad52 DNA Repair and Recombination Protein / genetics*
  • Synthetic Lethal Mutations
  • Tumor Suppressor p53-Binding Protein 1 / deficiency
  • Tumor Suppressor p53-Binding Protein 1 / genetics

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • Phthalazines
  • Piperazines
  • Rad52 DNA Repair and Recombination Protein
  • Rad52 protein, mouse
  • Tumor Suppressor p53-Binding Protein 1
  • Imatinib Mesylate
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1
  • Fusion Proteins, bcr-abl
  • olaparib