Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells
Year: 2018
Type: article
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.
Source: Cell Reports
Authors: 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
Institutions: Temple University, Drexel University, University of Pennsylvania, Fox Chase Cancer Center, Beckman Research Institute, Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, University of New Mexico, University of New Mexico Health Sciences Center, University of Alabama at Birmingham, UAB Medicine
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Awards: G1518942551, G2173646122, G270241475, G2766465774, Targeting PARP and RAD52 to induce "dual synthetic lethality" in leukemia patients identified by gene expression and mutation profiling, CD25-mediated feedback control of BCR-signaling and its oncogenic mimics, G7591350793, G8385465069, G8449081420, Central tolerance mechanisms in B-cell malignancies, Compensatory Mechanisms that Promote Homologous Recombination in BRCA1 Mutant Cancers
OpenAlex ID: W2808408940