Abstract:
The DNA damage response (DDR) mechanism includes the detection of DNA damage, suspension of the cell cycle, and initiation of DNA repair. Ataxia-telangiectasia and Rad3-related (ATR) protein is a key kinase involved in DDR. It is responsible for sensing replication stress (RS) and transmitting signals to S and G2/M checkpoints that initiate DNA repair. In tumor cells, the loss of G1-checkpoint control and activation of oncogenes that drive replication increase the probability of cancer cells entering the S phase, thus increasing RS. These cancer cells are more dependent on their S and G2/M checkpoints, making them attractive anti-cancer targets. Several potent, selective ATR inhibitors have been developed. Here, we summarize the clinical trial data supporting the application of ATR inhibitors for anticancer therapy, as single agents and in combination with chemotherapy, radiation therapy, and novel targeted drugs (such as PARP inhibitors). Subsequently, we discuss the current challenges in the development of ATR inhibitors and exploration of biomarkers.