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

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 leth...

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Detalles Bibliográficos
Autores principales: 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, Müschen, Markus, Bhatia, Smita, Bhatia, Ravi, Johnson, Neil, Wasik, Mariusz A., Mazin, Alexander V., Skorski, Tomasz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082171/
https://www.ncbi.nlm.nih.gov/pubmed/29898385
http://dx.doi.org/10.1016/j.celrep.2018.05.034
Descripción
Sumario: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.