Targeting DNA damage response pathways in cancer

Cells have evolved a complex network of biochemical pathways, collectively known as the DNA damage response (DDR), to prevent detrimental mutations from being passed on to their progeny. The DDR coordinates DNA repair with cell-cycle checkpoint activation and other global cellular responses. Due to compromised homologous recombination DNA repair, these tumours rely on alternative repair mechanisms. It is now clear that many other synthetic-lethal relationships exist between DDR genes. Crucially, some of these interactions could be exploited in the clinic to target tumours that become resistant to PARP inhibition. this Review discussed state-of-the-art strategies for DDR inactivation using small-molecule inhibitors and highlighted those compounds currently being evaluated in the clinic.