PARP Inhibitors: Mechanism of Action

Synthetic lethal therapy with poly(ADP-ribose) polymerase (PARP) inhibitors continues to attract attention as an effective treatment for hereditary breast and ovarian cancer (HBOC) with reduced DNA repair function because the treatment specifically causes high sensitivity in tumors. This effect is caused by the combination of PARP inhibitor-induced DNA double-strand break (DSB) formation and functional deficiency of homologous recombination (HR) repair, which is the main repair pathway for DNA damage. On the other hand, the clonal evolution in tumors as a tumor heterogeneity causes functional changes at each stage of the synthetic lethal pathway, resulting in the emergence of cancer cells with acquired resistance to PARP inhibitors. Various molecular mechanisms of the acquired resistance have been clarified. This chapter describes the synthetic lethal mechanism of PARP inhibitors, the mechanism of acquired resistance to PARP inhibitors, and the development of various PARP inhibitors.