Small-molecule drug repurposing to target DNA damage repair and response pathways.

For decades genotoxic therapy has been a mainstay in the treatment of cancer, based on the understanding that the deregulated growth and genomic instability that drive malignancy also confer a shared vulnerability. Although chemotherapy and radiation can be curative, only a fraction of patients benefit, while nearly all are subjected to the harmful side-effects. Drug repurposing, defined here as retooling existing drugs and compounds as chemo or radiosensitizers, offers an attractive route to identifying otherwise non-toxic agents that can potentiate the benefits of genotoxic cancer therapy to enhance the therapeutic ratio. This review seeks to highlight recent progress in defining cellular mechanisms of the DNA damage response including damage sensing, chromatin modification, DNA repair, checkpoint signaling, and downstream survival and death pathways, as a framework to determine which drugs and natural products may offer the most potential for repurposing as chemo- and/or radiosensitizers. We point to classical examples and recent progress that have identified drugs that disrupt cellular responses to DNA damage and may offer the greatest clinical potential. The most important next steps may be to initiate prospective clinical trials toward translating these laboratory discoveries to benefit patients.