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Cited by 331

The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.

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

Open access
Fok, Jacqueline H. L., Ramos-Montoya, Antonio, Vazquez-Chantada, Mercedes, Wijnhoven, Paul W. G., Follia, Valeria, James, Neil, Farrington, Paul M., Karmokar, Ankur, Willis, Sophie E., Cairns, Jonathan, Nikkilä, Jenni, Beattie, David, Lamont, Gillian M., Finlay, M. Raymond V., Wilson, Joanne, Smith, Aaron, O’Connor, Lenka Oplustil, Ling, Stephanie, Fawell, Stephen E., O’Connor, Mark J., Hollingsworth, Simon J., Dean, Emma, Goldberg, Frederick W., Davies, Barry R., Cadogan, Elaine B.·2019·Nature Communications
DOI 10.1038/s41467-019-12836-9
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Abstract

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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Metadata

Authors
Fok, J. H. L., Ramos-Montoya, A., Vazquez-Chantada, M., Wijnhoven, P. W. G., Follia, V., James, N., Farrington, P. M., Karmokar, A., Willis, S. E., Cairns, J., Nikkilä, J., Beattie, D., Lamont, G. M., Finlay, M. R. V., Wilson, J., Smith, A., O’Connor, L. O., Ling, S., Fawell, S. E., O’Connor, M. J., Hollingsworth, S. J., Dean, E., Goldberg, F. W., Davies, B. R., & Cadogan, E. B.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-11-07
Volume
10
Issue
1
Pages
5065-5065
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-019-12836-9
OpenAlex
W2985561224
Cited by
331
References
51
FWCI
11.43
Type
journal article
Language
en
Open access
gold

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The paper
Fok, J. H. L., Ramos-Montoya, A., Vazquez-Chantada, M., Wijnhoven, P. W. G., Follia, V., James, N., Farrington, P. M., Karmokar, A., Willis, S. E., Cairns, J., Nikkilä, J., Beattie, D., Lamont, G. M., Finlay, M. R. V., Wilson, J., Smith, A., O’Connor, L. O., Ling, S., Fawell, S. E., . . . Cadogan, E. B. (2019). AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity. Nature Communications. https://doi.org/10.1038/s41467-019-12836-9

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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.