Strategies towards more effective anticancer therapies: targeting DNA damage response pathways

The last decade has seen a tremendous increase in the understanding of the cellular mechanisms that underlie the detection and repair of DNA damage. This gave rise to the hypothesis that inhibition of DNA repair may result in increased efficacy of existing therapies and, more recently, to the idea that some tumor cells may carry additional defects that make them hypersensitive to DNA repair inhibitors as single agents. In order to minimize the potential to cause lesions in normal tissue, strategies have been directed to specific targets or pathways where selectivity for tumor over normal tissue is possible, thus to date most emphasis has been placed on a relatively small number of targets such as the poly(ADP-ribose) polymerase and the checkpoint kinases. Both of these approaches have yielded small molecule inhibitors that are currently in clinical trials.