Turning the concept of synthetic lethality on its head

One of the most significant discoveries in cancer treatment over the past 15 years has been the advent of poly(ADP-ribose) polymerase (PARP) inhibitors, and their exploitation of the concept of synthetic lethality in the treatment of BRCA1/2 mutant cancers (1,2). In synthetic lethality, the loss of each gene or protein by itself does not affect cell viability, but the loss of both results in cell death. The goal of this approach is to optimise targeted tumor cell death, while sparing normal tissue (the “magic bullet” first proposed by Paul Ehlrich in the late 19th century). PARP inhibitors in BRCA1/2 mutant tumors have been the classical example of this, where the loss of homologous recombination-mediated DNA repair through BRCA1/2 mutation renders cells sensitive to inhibition or loss of PARP1.