PARP inhibitors: the journey from research hypothesis to clinical approval.

Cancer puts an increasing burden on our healthcare system and is a major cause of death. Therefore, novel approaches are required to improve cancer treatment. Cancer cells have several hallmarks that could be therapeutically targeted. Importantly, every tumor has a different combination of aberrations affecting the different hallmarks. This review focuses on targeting one of these hallmarks, the DNA damage response (DDR). DDR defects can not only cause cancer, but they can also be exploited therapeutically. This plays an important role even in 'classical' (DNA damaging) chemotherapy and radiotherapy, but more precise targeting of specific defects is expected to increase treatment efficacy and decrease normal tissue toxicity. Poly-(ADP-ribose) polymerase (PARP) inhibitors are the first clinical example of such synthetic lethality in tumors having specific DDR defects. They are currently under investigation as DDR-targeting anticancer drugs and they progress quickly in clinical trials.