Abstract
ATR and ATM are DNA damage signaling kinases that phosphorylate several thousand substrates. ATR kinase activity is increased at damaged replication forks and resected DNA double-strand breaks (DSBs). ATM kinase activity is increased at DSBs. ATM has been widely studied since ataxia telangiectasia individuals who express no ATM protein are the most radiosensitive patients identified. Since ATM is not an essential protein, it is widely believed that ATM kinase inhibitors will be well-tolerated in the clinic. ATR has been widely studied, but advances have been complicated by the finding that ATR is an essential protein and it is widely believed that ATR kinase inhibitors will be toxic in the clinic. We describe AZD6738, an orally active and bioavailable ATR kinase inhibitor. AZD6738 induces cell death and senescence in non-small cell lung cancer (NSCLC) cell lines. AZD6738 potentiates the cytotoxicity of cisplatin and gemcitabine in NSCLC cell lines with intact ATM kinase signaling, and potently synergizes with cisplatin in ATM-deficient NSCLC cells. In contrast to expectations, daily administration of AZD6738 and ATR kinase inhibition for 14 consecutive days is tolerated in mice and enhances the therapeutic efficacy of cisplatin in xenograft models. Remarkably, the combination of cisplatin and AZD6738 resolves ATM-deficient lung cancer xenografts.
Highlights
ATR and ATM are apical DNA damage signaling kinases that phosphorylate a broad and overlapping catalogue of several thousand substrates [1,2,3]
Lung cancer cells are radiosensitized by pharmacologic ATM kinase inhibitors in tissue culture [8,9,10], and it is widely believed that ATM kinase inhibitors will be well-tolerated in the clinic as ATM is not an essential protein [7, 11]
A large margin of activity was observed for all targets tested relative to inhibition of ATR kinase-dependent kinase signaling (0.074 μM), with ATM, DNA-PK, and PI3Kα kinase inhibition all > 30 μM, and mTOR kinase inhibition > 23 μM (Supplementary Table S1)
Summary
ATR and ATM are apical DNA damage signaling kinases that phosphorylate a broad and overlapping catalogue of several thousand substrates [1,2,3]. ATR kinase activity is increased at damaged replication forks and resected DNA double-strand breaks (DSBs) [4]. ATM kinase activity is increased at DSBs [5]. ATM has been widely studied since individuals with the disease ataxia telangiectasia, who express no ATM protein, are the most radiosensitive patients identified [6, 7]. Lung cancer cells are radiosensitized by pharmacologic ATM kinase inhibitors in tissue culture [8,9,10], and it is widely believed that ATM kinase inhibitors will be well-tolerated in the clinic as ATM is not an essential protein [7, 11]. It is important to investigate the impact of ATM and ATR kinase inhibitors in preclinical models
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