Clinical potential of ATM inhibitors

The protein defective in the human genetic disorder ataxia-telangiectasia, ATM, plays a central role in re-sponding to DNA double strand breaks and other lesions to protect the genome against DNA damage and in this way minimize the risk of mutations that can lead to abnormal cellular behaviour. Its function in normal cells is to protect the cell against genotoxic stress but inadvertently it can assist cancer cells by providing resistance against chemotherapeutic agents and thus favouring tumour growth and survival. However, it is now evident that ATM also functions in a DNA damage-independent fashion to protect the cell against other forms of stress such as oxidative and nutrient stress and this non-canonical mechanism may also be relevant to cancer susceptibility in individuals who lack a functional ATM gene. Thus the use of ATM inhibitors to combat resistance in tumours may extend beyond a role for this protein in the DNA damage response. Here, we provide some background on ATM and its activation and investigate the efficacy of ATM inhibitors in treating cancer.