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. 2020 Aug 3;123(9):1424–1436. doi: 10.1038/s41416-020-1016-2

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© The Author(s) 2020

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 4 — a Immunoblot analysis of MIA PaCa-2 cells. Cells that received 6 Gy of γ-irradiation (IR) were harvested 30 min post-IR. All other samples were harvested after 24 h of drug exposure. ATRi + GEM denotes 2 µM AZD6738 and 30 nM gemcitabine. ATMi is AZD0156 and was either applied concurrently with ATRi/gem or administered 1 h prior to IR in the case of the two IR samples. b Immunoblot analysis of MIA PaCa-2 cells. Cells were harvested after 24 h of drug exposure. ATRi is AZD6738, ATMi is AZD0156, DNA-PKi is AZD7648. c Immunoblot analysis of HPAF-II cells. Cells were harvested after 24 h of drug exposure. d Immunoblot analysis of MIA PaCa-2 WT and MIA PaCa-2 ATM-KO cells (clone B7). Cells were harvested after 24 h of drug exposure. e Cells were treated with increasing concentrations of ATRi (AZD6738) and DNA-PKi (AZD7648) for 72 h, and growth was assessed by SRB assay. Top = growth as percentage of solvent control. Bottom = Combenefit synergy score (Loewe). Data, mean ± SD, n = 3. For matrices of all cell lines, see Fig. S3A. f Synergy comparison of the AZD6738 and AZD0156 combination (ATRi + ATMi, see Fig. S1) vs the AZD6738 and AZD7648 combination (ATRi + DNAPKi, Fig. S3A). Cells were treated with increasing concentrations for 72 h and growth as percentage of solvent control was assessed by SRB assay. Combenefit software was used to calculate the sum of synergy and antagonism across the dose ranges tested. g The effect of DNA-PK inhibition on AZD6783 and gemcitabine sensitivity in MIA PaCa-2. Values denote growth as percentage of solvent control (as assessed by SRB assay), mean ± SD, n = 3. h Visualisation of how much more effect ATM inhibition has compared to DNA-PK inhibition on the growth of ATRi/gem-treated MIAPaCa-2. Left = the %Control values of the MIA PaCa-2 + 1 µM DNA-PKi matrix from Fig. 4g were subtracted from those of the MIA PaCa-2 + DMSO matrix from Fig. 4g. Right = the %Control values of the MIA PaCa-2 + 30 nM ATMi matrix from Fig. 3a were subtracted from those of the MIA PaCa-2 + DMSO matrix from Fig. 3a.