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

Publication date: 12 June 2018
Source:Cell Reports, Volume 23, Issue 11
Author(s): Katherine Sullivan-Reed, Elisabeth Bolton-Gillespie, Yashodhara Dasgupta, Samantha Langer, Micheal Siciliano, Margaret Nieborowska-Skorska, Kritika Hanamshet, Elizaveta A. Belyaeva, Andrea J. Bernhardy, Jaewong Lee, Morgan Moore, Huaqing Zhao, Peter Valent, Ksenia Matlawska-Wasowska, Markus Müschen, Smita Bhatia, Ravi Bhatia, Neil Johnson, Mariusz A. Wasik, Alexander V. Mazin, Tomasz Skorski
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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Teaser

Sullivan-Reed et al. show that simultaneous treatment with PARP and RAD52 inhibitors exerts dual synthetic lethality in BRCA-deficient tumors. Addition of RAD52 inhibitor should improve therapeutic outcome of BRCA-deficient malignancies treated with PARP inhibitor.


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