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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2018
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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 |
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author | 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 |
author_facet | 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 |
author_sort | Sullivan-Reed, Katherine |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6082171 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
record_format | MEDLINE/PubMed |
spelling | pubmed-60821712018-08-08 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, 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 Cell Rep Article 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. 2018-06-12 /pmc/articles/PMC6082171/ /pubmed/29898385 http://dx.doi.org/10.1016/j.celrep.2018.05.034 Text en http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article 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 Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells |
title | Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells |
title_full | Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells |
title_fullStr | Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells |
title_full_unstemmed | Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells |
title_short | Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells |
title_sort | simultaneous targeting of parp1 and rad52 triggers dual synthetic lethality in brca-deficient tumor cells |
topic | Article |
url | 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 |
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