2. Academic Validation
  3. Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells

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

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: tskorski@temple.edu.
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z