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

2019; Nature Portfolio; Volume: 10; Issue: 1 Linguagem: Inglês

10.1038/s41467-019-12836-9

2041-1723

Jacqueline H. L. Fok, Antonio Ramos‐Montoya, Mercedes Vázquez–Chantada, Paul W.G. Wijnhoven, Valeria Follia, Neil H. James, Paul Farrington, Ankur Karmokar, Sophie E. Willis, Jonathan Cairns, Jenni Nikkilä, David T. 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, Elaine Cadogan,

Cell death mechanisms and regulation

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.