Targeting ATM and ATR for cancer therapeutics: inhibitors in clinic

Abstract

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.