The vast majority of
cancer patients receive
DNA-damaging drugs or ionizing radiation (IR) during their course of treatment, yet the efficacy of these
therapies is tempered by DNA repair and DNA damage response (DDR) pathways. Aberrations in DNA repair and the DDR are observed in many
cancer subtypes and can promote de novo
carcinogenesis,
genomic instability, and ensuing resistance to current
cancer therapy. Additionally, stalled or collapsed DNA replication forks present a unique challenge to the double-strand DNA break (
DSB) repair system. Of the various inducible DNA lesions, DSBs are the most lethal and thus desirable in the setting of
cancer treatment. In mammalian cells, DSBs are typically repaired by the error prone non-homologous end joining pathway (NHEJ) or the high-fidelity homology directed repair (HDR) pathway. Targeting
DSB repair pathways using small molecular inhibitors offers a promising mechanism to synergize
DNA-damaging drugs and IR while selective inhibition of the NHEJ pathway can induce synthetic lethality in HDR-deficient
cancer subtypes. Selective inhibitors of the NHEJ pathway and alternative
DSB-repair pathways may also see future use in precision genome editing to direct repair of resulting DSBs created by the HDR pathway. In this review, we highlight the recent advances in the development of inhibitors of the non-
phosphatidylinositol 3-kinase-related
kinases (non-PIKKs) members of the NHEJ, HDR and minor backup SSA and alt-NHEJ
DSB-repair pathways. The inhibitors described within this review target the non-PIKKs mediators of
DSB repair including Ku70/80, Artemis,
DNA Ligase IV, XRCC4, MRN complex, RPA, RAD51, RAD52, ERCC1-XPF, helicases, and
DNA polymerase θ. While the DDR PIKKs remain intensely pursued as therapeutic targets, small molecule inhibition of non-PIKKs represents an emerging opportunity in drug discovery that offers considerable potential to impact
cancer treatment.