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

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.

SUBMITTER: Sullivan-Reed K

PROVIDER: S-EPMC6082171 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Sullivan-Reed Katherine K Bolton-Gillespie Elisabeth E Dasgupta Yashodhara Y Langer Samantha S Siciliano Micheal M Nieborowska-Skorska Margaret M Hanamshet Kritika K Belyaeva Elizaveta A EA Bernhardy Andrea J AJ Lee Jaewong J Moore Morgan M Zhao Huaqing H Valent Peter P Matlawska-Wasowska Ksenia K Müschen Markus M Bhatia Smita S Bhatia Ravi R Johnson Neil N Wasik Mariusz A MA Mazin Alexander V AV Skorski Tomasz T

Cell reports 20180601 11

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 ...[more]

PMID: 29898385

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Project description:BackgroundCervical cancer is one of the most common cancers among females worldwide and advanced patients have extremely poor prognosis. However, adverse reactions and accumulating resistance to radiation therapy require further investigation.MethodsThe expression levels of mitogen-activated protein kinase 4 (MAPK4) mRNA were analyzed by real-time PCR and its association with overall survival was analyzed using Kaplan-Mier method. Colony formation, immunofluorescence and western blotting were used to examine the effects of MAPK4 knockout or over-expression on cervical cancer cells after radiation treatment. Drug-sensitivity of cervical cancer cells to PARP1 inhibitors, olaparib or veliparib, was analyzed by CCK-8 cell viability assays, and the 50% inhibitory concentration (IC50) was quantified using GraphPad Prism. The functional effects of MAPK4 knockout on the sensitivity of cervical cancer to radiation treatment and PARP1 inhibitors were further examined using xenograft tumor mouse models in vivo.ResultsCervical cancer patients with high MAPK4 mRNA expression have lower survival rate. After radiation treatment, the colony number of MAPK4 knockout cells was markedly reduced, and the markers for DNA double-chain breakage were significantly up-regulated. In addition, MAPK4 knockout reduced protein kinase B (AKT) phosphorylation, whereas its over-expression resulted in opposite effects. In MAPK4 KO cells with irradiation treatment, inhibition of AKT phosphorylation promoted DNA double-chain breakage. Constitutive activation of AKT (CA-AKT) increased the levels of phosphorylated-AKT (p-AKT), and DNA repair-related proteins, phosphorylated-DNA-dependent protein kinase (p-DNA-PK) and RAD51 recombinase (RAD51). Furthermore, MAPK4 knockout was found to affect the sensitivity of cervical cancer cells to poly ADP-ribose polymerase 1 (PARP1) inhibitors by activating the phosphorylation of AKT. Moreover, in vivo results demonstrated that MAPK4 knockout enhanced the sensitivity of cervical cancer to radiation and PARP1 inhibitors in mouse xenograft models.ConclusionsCollectively, our data suggest that combined application of MAPK4 knockout and PARP1 inhibition can be used as therapeutic strategy in radiation treatment for advanced cervical carcinoma.

Dataset Information

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

Publications

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

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