Cell reports. pii: S2211-1247(18)30780-0. doi: 10.1016/j.celrep.2018.05.034 |
Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells. |
Sullivan-Reed K1, Bolton-Gillespie E2, Dasgupta Y3, Langer S4, Siciliano M5, Nieborowska-Skorska M6, Hanamshet K7, Belyaeva EA8, Bernhardy AJ9, Lee J10, Moore M11, Zhao H12, Valent P13, Matlawska-Wasowska K14, Müschen M15, Bhatia S16, Bhatia R17, Johnson N18, Wasik MA19, Mazin AV20, Skorski T21 |
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. |
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved. |
KEYWORDS: BRCA-deficient tumors, PARP1, RAD52, synthetic lethality |
Publikations ID: 29898385 Quelle: öffnen |