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Sullivan-Reed K , Bolton-Gillespie E , Dasgupta Y , Langer S , Siciliano M , Nieborowska-Skorska M , Hanamshet K , Belyaeva EA , Bernhardy AJ , Lee J , Moore M , Zhao H , Valent P , Matlawska-Wasowska K , Muschen M , Bhatia S , Bhatia R , Johnson N , Wasik MA , Mazin AV , Skorski T
Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells
Cell Rep. 2018 Jun 12;23(11) :3127-3136
PMID: 29898385 PMCID: PMC6082171 URL: https://www.ncbi.nlm.nih.gov/pubmed/29898385
AbstractPARP 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.
Notes2211-1247 Sullivan-Reed, Katherine Bolton-Gillespie, Elisabeth Dasgupta, Yashodhara Langer, Samantha Siciliano, Micheal Nieborowska-Skorska, Margaret Hanamshet, Kritika Belyaeva, Elizaveta A Bernhardy, Andrea J Lee, Jaewong Moore, Morgan Zhao, Huaqing Valent, Peter Matlawska-Wasowska, Ksenia Muschen, Markus Bhatia, Smita Bhatia, Ravi Johnson, Neil Wasik, Mariusz A Mazin, Alexander V Skorski, Tomasz Journal Article United States Cell Rep. 2018 Jun 12;23(11):3127-3136. doi: 10.1016/j.celrep.2018.05.034.