DNA repair pathways as targets for cancer therapy

Several cancer chemotherapy drugs work by producing excessive DNA damage that causes cell death directly or following DNA replication. Survival is promoted through repair of these lesions by a number of DNA repair pathways.The efficacy of anticancer drugs is highly influenced by cellular DNA repair capacity. Inhibitors of DNA repair increase the efficacy of DNA-damaging anticancer drugs in preclinical models. Small-molecule inhibitors of DNA repair have been combined with conventional chemotherapy drugs in several phase I–II clinical trials.Tumour development can be associated with perturbed DNA damage response and repair pathways. This perturbation results in reduced DNA repair capacity and increased genetic instability in tumour cells. Defects in one DNA repair pathway can be compensated for by other pathways. Such compensating pathways can be identified in synthetic lethality screens and then specifically targeted for treatment of DNA repair-defective tumours.Evidence indicates that inhibitors of DNA repair pathways can work as single agents for the targeted treatment of DNA repair-defective cancers. This hypothesis is currently being tested in phase II trials in which patients with breast or ovarian cancers that are defective in homologous recombination are being treated with a poly(ADP-ribose) polymerase inhibitor.Tumours often exhibit replication stress as a consequence of oncogene-induced growth signals or hypoxia-induced replication arrest. We propose that DNA repair inhibitors could be used to prevent the repair of replication lesions present in tumour cells and convert them into fatal replication lesions that specifically kill cancer cells.