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
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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