Targeting ATM and ATR for cancer therapeutics: Inhibitors in clinic

The DNA Damage and Response (DDR) pathway ensures accurate information transfer from one generation to the next. Alterations in DDR functions have been connected to cancer predisposition, progression, and response to therapy. DNA double-strand break (DSB) is one of the most detrimental DNA defects, causing major chromosomal abnormalities such as translocations and deletions. ATR and ATM kinases recognize this damage and activate proteins involved in cell cycle checkpoint, DNA repair, and apoptosis. Cancer cells have a high DSB burden, and therefore rely on DSB repair for survival. Therefore, targeting DSB repair can sensitize cancer cells to DNA-damaging agents. This review focuses on ATM and ATR, their roles in DNA damage and repair pathways, challenges in targeting them, and inhibitors that are in current clinical trials.

Automated summary

The DNA Damage and Response (DDR) pathway is crucial for maintaining genome integrity and preventing cancer development. The DDR pathway, particularly the ATM and ATR kinases, plays a vital role in recognizing and repairing DNA double-strand breaks (DSBs), a severe DNA damage that can lead to genomic instability. Cancer cells, with a high burden of DSBs, heavily rely on efficient DSB repair mechanisms for their survival. Therefore, targeting DSB repair pathways, such as ATM and ATR, can enhance the efficacy of DNA-damaging agents in cancer treatment. This review focuses on the roles of ATM and ATR in the DDR pathway, challenges in targeting these kinases, and current clinical trials of their inhibitors.