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

Jacqueline H. L. Fok, Antonio Ramos-Montoya, Mercedes Vazquez-Chantada, Paul W. G. Wijnhoven, Valeria Follia, Neil James, Paul M. Farrington, Ankur Karmokar, Sophie E. Willis, Jonathan Cairns, Jenni Nikkilä, David Beattie, Gillian M. Lamont, M. Raymond V. Finlay, Joanne Wilson, Aaron Smith, Lenka Oplustil O’Connor, Stephanie Ling, Stephen E. Fawell, Mark J. O’Connor, Simon J. Hollingsworth, Emma Dean, Frederick W. Goldberg, Barry R. Davies and Elaine B. Cadogan ()
Additional contact information
Jacqueline H. L. Fok: AstraZeneca
Antonio Ramos-Montoya: AstraZeneca
Mercedes Vazquez-Chantada: AstraZeneca
Paul W. G. Wijnhoven: AstraZeneca
Valeria Follia: AstraZeneca
Neil James: AstraZeneca
Paul M. Farrington: AstraZeneca
Ankur Karmokar: AstraZeneca
Sophie E. Willis: AstraZeneca
Jonathan Cairns: AstraZeneca
Jenni Nikkilä: AstraZeneca
David Beattie: AstraZeneca
Gillian M. Lamont: AstraZeneca
M. Raymond V. Finlay: AstraZeneca
Joanne Wilson: AstraZeneca
Aaron Smith: AstraZeneca
Lenka Oplustil O’Connor: AstraZeneca
Stephanie Ling: AstraZeneca
Stephen E. Fawell: AstraZeneca
Mark J. O’Connor: AstraZeneca
Simon J. Hollingsworth: AstraZeneca
Emma Dean: AstraZeneca
Frederick W. Goldberg: AstraZeneca
Barry R. Davies: AstraZeneca
Elaine B. Cadogan: AstraZeneca

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12836-9

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