Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Oncotarget	6	42	2015 Dec 29	44289-305	Oncotarget

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 + Ceralasertib	Acalabrutinib Ceralasertib	0	1
Ceralasertib	Ceralasertib	9	8

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Ceralasertib		AZD6738\|AZD-6738	ATR Inhibitor 16	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	Ceralasertib + 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