Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

In order to maintain genomic stability, cells have developed sophisticated signalling pathways to enable DNA damage or DNA replication stress to be resolved. Key mediators of this DNA damage response (DDR) are the ATM and ATR kinases, which induce cell cycle arrest and facilitate DNA repair via their downstream targets. Inhibiting the DDR has become an attractive therapeutic concept in cancer therapy, since (i) resistance to genotoxic therapies has been associated with increased DDR signalling, and (ii) many cancers have defects in certain components of the DDR rendering them highly dependent on the remaining DDR pathways for survival. ATM and ATR act as the apical regulators of the response to DNA double strand breaks and replication stress, respectively, with overlapping but non-redundant activities. Highly selective small molecule inhibitors of ATM and ATR are currently in preclinical and clinical development, respectively. Preclinical data have provided a strong rationale for clinical testing of these compounds both in combination with radio- or chemotherapy, and in synthetic lethal approaches to treat tumours with deficiencies in certain DDR components. Whole genome sequencing studies have reported that mutations in DDR genes occur with a high frequency in many common tumour types, suggesting that a synthetic lethal approach with ATM or ATR inhibitors could have widespread utility, providing that appropriate biomarkers are developed.

Original publication




Journal article


Pharmacol Ther

Publication Date





124 - 138


ATM, ATR, DNA damage response, Synthetic lethality, Animals, Ataxia Telangiectasia Mutated Proteins, DNA Damage, Humans, Models, Biological, Molecular Targeted Therapy, Neoplasms, Patient Selection, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Signal Transduction