Missense mutations in ATM kinase, a master regulator of DNA damage responses, are found in many cancers, but their impact on ATM function and implications for cancer therapy are largely unknown. Here we report that 72% of cancer-associated ATM mutations are missense mutations that are enriched around the kinase domain. Expression of kinase-dead ATM (AtmKD/-) is more oncogenic than loss of ATM (Atm-/-) in mouse models, leading to earlier and more frequent lymphomas with Pten deletions. Kinase-dead ATM protein (Atm-KD), but not loss of ATM (Atm-null), prevents replication-dependent removal of Topo-isomerase I-DNA adducts at the step of strand cleavage, leading to severe genomic instability and hypersensitivity to Topo-isomerase I inhibitors. Correspondingly, Topo-isomerase I inhibitors effectively and preferentially eliminate AtmKD/-, but not Atm-proficientor Atm-/- leukemia in animal models. These findings identify ATM kinase-domain missense mutations as a potent oncogenic event and a biomarker for Topo-isomerase I inhibitor based therapy.Cancer is a genetic disease. To remain healthy, therefore, it is essential that cells do not accrue too many dangerous mutations in their DNA that allow cancers to grow and develop. An enzyme called ATM helps to do just that. DNA damage activates ATM, which, in turn, adds phosphate groups to other proteins. These newly tagged proteins then stop cells dividing until the DNA has been repaired.Human cancers often switch off ATM, either by completely deleting the enzyme or mutating it. This renders ATM unable to add phosphate groups to proteins, and so allows the cancer cells to continue proliferating even in the face of DNA damage.Yamamoto et al. wanted to know whether cancers that completely lack ATM behave differently from cancers that contain an inactive version of the enzyme. Studying mice that were engineered to have an inactive version of ATM in their blood cells showed that such mice developed blood cancers faster than mice have no ATM in their blood cells. In particular, cancer cells with the inactive form of the ATM enzyme accumulated more DNA damage than cells that lacked the enzyme completely.Using biochemical techniques, Yamamoto et al. then showed that the inactive form of ATM can prevent other enzymes from repairing DNA. Drugs that inhibit one of these repair enzymes – called topo-isomerase I – are already used in cancer treatments. These drugs were particularly effective on tumors with the inactive version of the ATM enzyme.As ATM is commonly mutated in human cancers, the next steps that follow on from this research are to develop methods to test which cancers contain the inactive form of the ATM enzyme. Clinical trials could then investigate how effectively topo-isomerase I inhibitors treat these specific types of cancer.
Yamamoto, K., Wang, J., Sprinzen, L., Xu, J., Haddock, C. J., Li, C., … Zha, S. (2016). Kinase-dead ATM protein is highly oncogenic and can be preferentially targeted by Topo-isomerase I inhibitors. ELife, 5. https://doi.org/10.7554/elife.14709