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

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    Genre
    Thesis/Dissertation
    Date
    2018
    Author
    Reed, Katherine Sullivan
    Advisor
    Skorski, Tomasz
    Committee member
    Soprano, Dianne R.
    Graña-Amat, Xavier
    Liebermann, Dan A., 1949-
    Pomerantz, Richard
    Johnson, Neil
    Mazin, Alexander
    Department
    Biomedical Sciences
    Subject
    Oncology
    Cellular Biology
    Brca
    Dna Repair
    Parp1
    Rad52
    Synthetic Lethality
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/3460
    
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    DOI
    http://dx.doi.org/10.34944/dspace/3442
    Abstract
    PARP inhibitors (PARPi) have been used to induce synthetic lethality in BRCA-deficient tumors in clinical trials with limited success due to the development of resistance to PARPi. BRCA-deficient cells are unable to repair DNA double strand breaks by the accurate homologous recombination repair (HR), and therefore rely on alternative DNA repair pathways for survival. We hypothesized that RAD52-mediated DNA repair mechanisms remain active and are thus protecting some PARPi-treated BRCA-deficient tumor cells from apoptosis, and that targeting RAD52 should enhance the synthetic lethal effect of PARPi. We show here that RAD52 inhibitors (RAD52i) attenuated single-strand annealing (SSA) and residual HR activity in BRCA-deficient cells. Simultaneous targeting of PARP1 and RAD52 with small molecule inhibitors or via expression of dominant-negative mutants induced an accumulation of DSBs and selective eradication of BRCA-deficient solid tumor and leukemia cells, while BRCA-proficient cells were unaffected. Parp1-/-Rad52-/- transgenic mice are healthy and indistinguishable from wild-type mice due to the presence of the BRCA-pathway, and Parp1-/-Rad52-/- mice with inducible BRCA1-deficient leukemia displayed significantly prolonged survival when compared to Parp1-/- and Rad52-/- counterparts. Finally, PARPi + RAD52i selectively targeted BRCA1-deficient solid tumors in immunodeficient mice with minimal toxicity to normal cells and tissues which are protected by the BRCA-pathway, indicating minimal side effects. In conclusion, our data indicate that combination treatment of RAD52i and PARPi will significantly improve therapeutic outcome of BRCA-deficient malignancies compared to treatment with PARPi monotherapy, while leaving healthy cells and tissues unharmed.
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