Reference Detail

Ref Type

Journal Article

PMID

(31699977)

Authors

Fok JHL, Ramos-Montoya A, Vazquez-Chantada M, Wijnhoven PWG, Follia V, James N, Farrington PM, Karmokar A, Willis SE, Cairns J, Nikkilä J, Beattie D, Lamont GM, Finlay MRV, Wilson J, Smith A, O'Connor LO, Ling S, Fawell SE, O'Connor MJ, Hollingsworth SJ, Dean E, Goldberg FW, Davies BR, Cadogan EB

Title

AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature communications	10	1	2019 Nov 07	5065	Nat Commun

URL

Abstract Text

DNA-dependent protein kinase (DNA-PK) is a critical player in the DNA damage response (DDR) and instrumental in the non-homologous end-joining pathway (NHEJ) used to detect and repair DNA double-strand breaks (DSBs). We demonstrate that the potent and highly selective DNA-PK inhibitor, AZD7648, is an efficient sensitizer of radiation- and doxorubicin-induced DNA damage, with combinations in xenograft and patient-derived xenograft (PDX) models inducing sustained regressions. Using ATM-deficient cells, we demonstrate that AZD7648, in combination with the PARP inhibitor olaparib, increases genomic instability, resulting in cell growth inhibition and apoptosis. AZD7648 enhanced olaparib efficacy across a range of doses and schedules in xenograft and PDX models, enabling sustained tumour regression and providing a clear rationale for its clinical investigation. Through its differentiated mechanism of action as an NHEJ inhibitor, AZD7648 complements the current armamentarium of DDR-targeted agents and has potential in combination with these agents to achieve deeper responses to current therapies.

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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
AZD7648	AZD7648	3	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AZD7648		AZD-7648\|AZD 7648	DNA_PK Inhibitor 9	AZD7648 is an inhibitor of DNA-dependent protein kinase (DNA-PK), which potentially enhances genomic instability and sensitizes tumor cells to DNA-damaging agents (PMID: 31699977, PMID: 31851518).

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
TP53 mutant	ovarian cancer	sensitive	AZD7648	Preclinical - Pdx	Actionable	In a preclinical study, AZD7648 treatment inhibited tumor growth in a patient-derived xenograft (PDX) model of ovarian cancer harboring a TP53 mutation and wild-type ATM (PMID: 31699977).	31699977
ATM del	lung non-small cell carcinoma	sensitive	Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, Lynparza (olaparib) treatment inhibited viability of ATM knockout non-small cell lung carcinoma cells in culture (PMID: 31699977).	31699977
TP53 mutant	ovarian cancer	predicted - sensitive	Olaparib	Preclinical - Pdx	Actionable	In a preclinical study, Lynparza (olaparib) treatment inhibited tumor growth but did not induce regression in a patient-derived xenograft (PDX) model of ovarian cancer harboring wild-type ATM and TP53 mutation (PMID: 31699977).	31699977
ATM del	lung non-small cell carcinoma	sensitive	AZD7648 + Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, AZD7648 treatment increased sensitivity to Lynparza (olaparib), inducing cell cycle arrest and inhibiting viability of ATM knockout non-small cell lung carcinoma cells in culture (PMID: 31699977).	31699977
ATM del	lung non-small cell carcinoma	sensitive	AZD7648	Preclinical - Cell culture	Actionable	In a preclinical study, AZD7648 treatment inhibited viability of ATM knockout non-small cell lung carcinoma cells in culture (PMID: 31699977).	31699977
ATM del	head and neck cancer	sensitive	AZD7648 + Olaparib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, AZD7648 treatment increased sensitivity to Lynparza (olaparib), resulting in inhibition of Dna-pk phosphorylation, reduced cell viability, genomic instability, cell cycle arrest, and apoptosis in a head and neck cancer cell line with ATM deletion in culture, and inhibition of tumor growth and complete tumor regression in a cell line xenograft model (PMID: 31699977).	31699977
TP53 mutant	ovarian cancer	predicted - sensitive	AZD7648 + Olaparib	Preclinical - Pdx	Actionable	In a preclinical study, AZD7648 and Lynparza (olaparib) combination treatment induced tumor regression in a patient-derived xenograft (PDX) model of ovarian cancer harboring TP53 mutation and wild-type ATM (PMID: 31699977).	31699977
ATM del	head and neck cancer	sensitive	AZD7648	Preclinical - Cell culture	Actionable	In a preclinical study, AZD7648 treatment induced genomic instability, cell cycle arrest, and inhibited viability of an ATM knockout head and neck cancer cell line in culture (PMID: 31699977).	31699977
ATM del	head and neck cancer	sensitive	Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, Lynparza (olaparib) treatment induced genomic instability, cell cycle arrest, and inhibited viability of an ATM knockout head and neck cancer cell line in culture (PMID: 31699977).	31699977