Kinase-dead ATM protein is highly oncogenic and can be preferentially targeted by Topo-isomerase I inhibitors

Abstract

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.DOI: http://dx.doi.org/10.7554/eLife.14709.001

ATM directs DNA damage responses and proteostasis via genetically separable pathways

“…For comparison, we also tested cells expressing the kinase-deficient D2889A (DA) mutant allele of ATM (33) which exhibited extremely poor survival of both ionizing radiation and CPT (Fig. S4), clearly worse than the ATM-depleted cells with no complementation, suggestive of a dominant negative effect (34). …”

“…Lastly, it is important to investigate the basis of the extreme dominant-negative effect of kinase-deficient ATM on cells. This is almost certainly related to the embryonic lethal phenotype of this allele in the mouse (33, 34), but it is currently unknown whether this is caused by stable binding of the mutant ATM to certain substrates and if so, which substrates are the cause of the cellular toxicity during stress responses and during development.…”

Proteomic Screening and Lasso Regression Reveal Differential Signaling in Insulin and Insulin-like Growth Factor I (IGF1) Pathways

“…These observations led to the study of the individual interaction values only. First, the set of nonself-interactions present in TT matrices of both IGF1 and Ins stimulation cases were determined (96,87,98,78,62, and 85 interactions found for time points 1-6, respectively). The list was filtered to retain only pairs of interactions having either phospho-Akt (pAkt) or phospho-MAPK (pMAPK) as outputs because these are two of the major downstream mediators of IGF1 and Ins signaling.…”

“…Further study of that interaction might spearhead new combination therapies with IGF1R inhibitors in breast cancer tumors. Indeed, very recently, researchers have shown that presence of kinase-domain mutations in ATM is a biomarker for Topo-isomerase I inhibitor therapy (98).…”

Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer

“…Monoallelic ATM mutation in carriers also leads to a significant increase in breast cancer risk (~2-fold) (Renwick et al 2006, Thompson et al 2005). Most ATM mutations associated with A-T are truncations; however, studies suggest that those associated with cancers tend to be missense mutations, frequently in the kinase domain of ATM (Scott et al 2002, Yamamoto et al 2016). Inhibition of ATM kinase activity promotes the transformation of normal human mammary epithelial cells, consistent with its association with breast cancer suppression (Mandriota et al 2010).…”