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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 Nature communications
Vol 10
Issue 1
Date 2019 Nov 07
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
Drug Name Trade Name Synonyms Drug Classes Drug Description
AZD7648 AZD-7648|AZD 7648 DNA_PK Inhibitor 6 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
Unknown unknown ovarian cancer not applicable AZD7648 + Olaparib Preclinical - Cell culture Actionable In a preclinical study, AZD7648 and Lynparza (olaparib) combination treatment inhibited viability of ovarian cancer cell lines harboring wild-type ATM in culture (PMID: 31699977). 31699977
Unknown unknown head and neck cancer not applicable AZD7648 Preclinical - Pdx Actionable In a preclinical study, AZD7648 treatment inhibited tumor growth in a patient-derived xenograft (PDX) model of head and neck cancer harboring mutant TP53 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
Unknown unknown breast cancer not applicable AZD7648 Preclinical - Cell line xenograft Actionable In a preclinical study, AZD7648 treatment inhibited tumor growth in a cell line xenograft model of breast cancer, however, with decreased response compared to AZD7648 and Doxil (pegylated liposomal-doxorubicin) combination treatment (PMID: 31699977). 31699977
Unknown unknown breast cancer not applicable AZD7648 + Pegylated liposomal-doxorubicin Preclinical - Cell line xenograft Actionable In a preclinical study, AZD7648 and Doxil (pegylated liposomal-doxorubicin) combination treatment synergistically inhibited growth of breast cancer cell lines in culture, and inhibited tumor growth and induced regression in a cell line xenograft model (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
Unknown unknown head and neck cancer not applicable AZD7648 + Olaparib Preclinical - Pdx Actionable In a preclinical study, AZD7648 and Lynparza (olaparib) combination treatment inhibited tumor growth in a patient-derived xenograft (PDX) model of head and neck cancer harboring mutant TP53 and wild-type ATM (PMID: 31699977). 31699977
Unknown unknown head and neck cancer not applicable Olaparib Preclinical - Pdx Actionable In a preclinical study, a patient-dervived xenograft (PDX) model of head and neck cancer harboring mutant TP53 and wild-type ATM did not demonstrate sensitivity to Lynparza (olaparib) treatment (PMID: 31699977). 31699977
Unknown unknown ovarian cancer not applicable AZD7648 + Pegylated liposomal-doxorubicin Preclinical - Cell culture Actionable In a preclinical study, AZD7648 and Doxil (pegylated liposomal-doxorubicin) combination treatment induced DNA damage and synergistically inhibited viability of ovarian cancer cell lines in culture (PMID: 31699977). 31699977
Unknown unknown lung non-small cell carcinoma not applicable AZD7648 Preclinical - Cell line xenograft Actionable In a preclinical study, AZD7648 did not inhibit tumor growth in cell line xenograft models of non-small cell lung carcinoma (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
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
Unknown unknown lung non-small cell carcinoma not applicable AZD7648 + Radiotherapy Preclinical - Cell line xenograft Actionable In a preclinical study, AZD7648 treatment increased sensitivity to radiotherapy, inhibiting proliferation and inducing cell cycle arrest in non-small cell lung carcinoma cells in culture, and inhibiting tumor growth and inducing tumor regression in cell line xenograft models (PMID: 31699977). 31699977