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Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells
Sullivan-Reed, Katherine Bolton-Gillespie, Elisabeth Dasgupta, Yashodhara Langer, Samantha Siciliano, Michael Nieborowska-Skorska, Margaret Hanamshet, Kritika Belyaeva, Elizaveta A. Bernhardy, Andrea J. Lee, Jaewong
Sullivan-Reed, Katherine
Bolton-Gillespie, Elisabeth
Dasgupta, Yashodhara
Langer, Samantha
Siciliano, Michael
Nieborowska-Skorska, Margaret
Hanamshet, Kritika
Belyaeva, Elizaveta A.
Bernhardy, Andrea J.
Lee, Jaewong
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Journal article
Date
2018-06-12
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Microbiology and Immunology
Clinical Sciences
Clinical Sciences
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https://doi.org/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.
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Cell Press
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Cell Reports, Vol. 23, Iss. 11
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