Inhibition of DNA-PK with AZD7648 sensitizes tumor cells to radiotherapy and induces type I IFN-dependent durable tumor control
Farrington, Paul M
James, Neil H
Bickerton, Susan J
Hughes, G. D.
Illidge, Timothy M
Cadogan, E. B.
Davies, B. R.
Dovedi, S. J
AffiliationBioscience, Early Oncology, Oncology R&D, AstraZeneca, Alderley Park, Macclesfield
MetadataShow full item record
AbstractPurpose: Combining radiotherapy (RT) with DNA damage response inhibitors may lead to increased tumor cell death through radiosensitization. DNA-dependent protein kinase (DNA-PK) plays an important role in DNA double-strand break repair via the nonhomologous end joining (NHEJ) pathway. We hypothesized that in addition to a radiosensitizing effect from the combination of RT with AZD7648, a potent and specific inhibitor of DNA-PK, combination therapy may also lead to modulation of an anticancer immune response. Experimental design: AZD7648 and RT efficacy, as monotherapy and in combination, was investigated in fully immunocompetent mice in MC38, CT26, and B16-F10 models. Immunologic consequences were analyzed by gene expression and flow-cytometric analysis. Results: AZD7648, when delivered in combination with RT, induced complete tumor regressions in a significant proportion of mice. The antitumor efficacy was dependent on the presence of CD8+ T cells but independent of NK cells. Analysis of the tumor microenvironment revealed a reduction in T-cell PD-1 expression, increased NK-cell granzyme B expression, and elevated type I IFN signaling in mice treated with the combination when compared with RT treatment alone. Blocking of the type I IFN receptor in vivo also demonstrated a critical role for type I IFN in tumor growth control following combined therapy. Finally, this combination was able to generate tumor antigen-specific immunologic memory capable of suppressing tumor growth following rechallenge. Conclusions: Blocking the NHEJ DNA repair pathway with AZD7648 in combination with RT leads to durable immune-mediated tumor control.
CitationNakamura K, Karmokar A, Farrington PM, James NH, Ramos-Montoya A, Bickerton SJ, et al. Inhibition of DNA-PK with AZD7648 Sensitizes Tumor Cells to Radiotherapy and Induces Type I IFN-Dependent Durable Tumor Control. Clin Cancer Res. 2021 May 19;27(15):4353–66.
JournalClinical Cancer Research
- AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity.
- 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
- Issue date: 2019 Nov 7
- The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-<i>a</i>]pyridin-6-yl)amino]-9-(tetrahydro-2<i>H</i>-pyran-4-yl)-7,9-dihydro-8<i>H</i>-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor.
- Authors: Goldberg FW, Finlay MRV, Ting AKT, Beattie D, Lamont GM, Fallan C, Wrigley GL, Schimpl M, Howard MR, Williamson B, Vazquez-Chantada M, Barratt DG, Davies BR, Cadogan EB, Ramos-Montoya A, Dean E
- Issue date: 2020 Apr 9
- The DNA-PK Inhibitor AZD7648 Sensitizes Patient-Derived Ovarian Cancer Xenografts to Pegylated Liposomal Doxorubicin and Olaparib Preventing Abdominal Metastases.
- Authors: Anastasia A, Dellavedova G, Ramos-Montoya A, James N, Chiorino G, Russo M, Baakza H, Wilson J, Ghilardi C, Cadogan EB, Giavazzi R, Bani MR
- Issue date: 2022 Apr 1
- Radiosensitisation of SCCVII tumours and normal tissues in mice by the DNA-dependent protein kinase inhibitor AZD7648.
- Authors: Hong CR, Buckley CD, Wong WW, Anekal PV, Dickson BD, Bogle G, Hicks KO, Hay MP, Wilson WR
- Issue date: 2022 Jan
- Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441.
- Authors: Zhao Y, Thomas HD, Batey MA, Cowell IG, Richardson CJ, Griffin RJ, Calvert AH, Newell DR, Smith GC, Curtin NJ
- Issue date: 2006 May 15