Activation-Induced Cytidine Deaminase (AID) mutates and modifies the IgH locus. However, it also initiates double-strand breaks (DSBs) throughout the genome. This effect of AID is balanced by RAD51-dependent homologous recombination repair. Importantly, we previously showed that inhibition of RAD51 function by a small-molecule inhibitor leads to cell death of AID-positive neoplastic cells. While we have used AID-RAD51 imbalance as a potential chemotherapy approach, the efficacy of current RAD51 inhibitors can be further improved. Studies have shown a relationship between glycolysis and RAD51 function, and therefore targeting the glycolytic pathway is a viable strategy to enhance RAD51 inhibitor efficacy. Here we show that glycolytic inhibitor 2DG and RAD51 inhibitor DIDS act synergistically to reduce B-lymphocyte human chronic lymphocytic leukemia proliferation ex vivo, and mice xenografted with this cell line showed significant reduction in the tumor burden in the presence of both 2DG and DIDS. These data suggest that the glycolytic pathway and DNA repair can be simultaneously targeted to produce better chemotherapies against B-lymphoid cancers.
Citation Format: Muneer G. Hasham, Kin-hoe Chow, John Wilson, Nathan LaBrie, Bryant Perkins, Jane Branca, Thomas Sproule, Derry Roopenian. Targeting glycolysis and RAD51-dependent repair in B-lymphoid cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A115.
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