DNA damage response and repair (DDR) is responsible for ensuring genomic integrity. It is composed of intricate, complex pathways that detect various DNA insults and then activate pathways to restore DNA fidelity. Mutations in this network are implicated in many malignancies but can also be exploited for cancer therapies. The advent of inhibitors of poly(ADP-ribose) polymerase has led to the investigation of other DDR inhibitors and combinations to address high unmet needs in cancer therapeutics. Specifically, regimens, often in combination with chemotherapy, radiation, or other DDR inhibitors, are being investigated. This review will focus on 4 main DDR pathways-ATR/CHK1, ATM/CHK2, DNA-PKcs, and polymerase θ-and the current state of clinical research and use of the inhibitors of these pathways with other DDR inhibitors.
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