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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 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 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 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
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
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 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 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