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Ref Type Journal Article
PMID (26517239)
Authors Vendetti FP, Lau A, Schamus S, Conrads TP, O'Connor MJ, Bakkenist CJ
Title The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo.
Journal Oncotarget
Vol 6
Issue 42
Date 2015 Dec 29
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Acalabrutinib + AZD6738 AZD6738 Acalabrutinib 0 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
AZD6738 Ceralasertib|AZD-6738 ATR Inhibitor 12 Ceralasertib (AZD6738) is an inhibitor of ATR, which may enhance the sensitivity of chemotherapeutic agents, potentially resulting in tumor regression (PMID: 26517239, PMID: 31836456).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ATM loss lung non-small cell carcinoma sensitive AZD6738 + Cisplatin Preclinical Actionable In a preclinical study, AZD6738 and Platinol (cisplatin) synergistically induced cell death in ATM-deficient non-small cell lung carcinoma cell lines in culture, and caused rapid tumor regression in xenograft models (PMID: 26517239). 26517239