Fig. 5.

AZD7648 and olaparib combination has antiproliferative efficacy. a Western blot analysis of whole-cell lysates from FaDu WT or ATM KO cells treated with AZD7648 (0.6 μM), olaparib (0.1, 0.3 or 1 μM) or the combination for 24 hours. Both cell lines were run on the same blot. b Cell confluency of FaDu ATM KO and WT cells treated with AZD7648, olaparib or their combination. Graphs represent mean percentage cell confluency from a representative experiment (n = 4). Percentage values indicate final cell confluency at the indicated time point. c AZD7648 induces complete tumour regression in combination with olaparib in FaDu ATM KO xenografts (SCID mice, vehicle n = 6, olaparib n = 10, AZD7648 37.5 and 75 mg kg⁻¹ single agent and combination at 37.5 mg kg⁻¹ n = 8, combination at 75 mg kg⁻¹ n = 11, geometric mean ± SEM). Corresponding mouse bodyweights and statistical analysis can be found in Supplementary Fig. 2E and Supplementary Table 3C. To assess tumour growth inhibition, one-tailed, two-sample, t-test with unequal variances was used and for tumour regression, one-sample t-test analysis. d Pharmacokinetics of AZD7648 and pharmacodynamic modulation of DNA-PK biomarkers after dosing of AZD7648 and olaparib in FaDu ATM KO xenografts. Mice were taken from the efficacy study described above (c) between days 11 and 18, and samples were collected 2 h after the first dose of AZD7648 (1 h after the dose of olaparib). Measured by western blotting (SCID mice, vehicle n = 10, olaparib n = 11, AZD7648 n = 12, combination n = 3, mean ± SEM). Significance assessed with two-sided t-tests performed on log-transformed data assuming unequal variance