Fig. 2

DDR inhibitors mechanisms and targeted pathways in the clinic. (left) The mechanism of DDR inhibitors; DDR inhibitors inhibit the DDR proteins from repairing DNA SSBs, resulting in collapsed replication forks, which leads to DNA DSBs and tumor cell apoptosis. (right) DDR pathways repair DNA through the mitigation of replication stress, therefore the inhibition of these pathways by DDR inhibitors resulted in SSBs and DSBs accumulation. DNA replication is crucial for the DNA repair process, which is associated with replicative stress response and cell cycle regulation. ATM and ATR kinases maintain replication fork stability and regulate the cell cycle control checkpoints together with CHK1/2. The main DDR inhibitors that are currently undergoing clinical trials target the major components of the DDR pathways. The major potential resistance to DDR inhibitors centers around three general mechanisms: replication fork protection, cell cycle arrest, and HR restoration. DDR DNA damage response, SSB single-strand break, DSB double-strand break, PARP poly(ADP-ribose) polymerase, PARG, poly(ADP-ribose) glycohydrolase, PARylation polyADP-ribosylation, HR homologous recombination