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- Title
AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity.
- Authors
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.
- 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. DNA-dependent protein kinase (DNA-PK) plays a major role in the DNA damage response upon double-strand break formation. Here, the authors show that the DNA-PK inhibitor AZD7648, enhances the activity of radiotherapy, chemotherapy and the PARP inhibitor olaparib in multiple mouse tumour models.
- Subjects
PROTEIN kinases; PROTEIN kinase inhibitors; RADIATION; CANCER chemotherapy; DOXORUBICIN
- Publication
Nature Communications, 2019, Vol 10, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-12836-9