Fig 5. Investigating AZD7648 exposure parameters to maximise olaparib combination efficacy.

(A) In vivo and Microformulator-replicated PK profile of olaparib (50 mg/kg QD) and fixed IC₉₀ and IC₅₀ concentrations for DNA-PK AZD7648. (B) Durations of daily exposure to AZD7648 at either IC₉₀ or IC₅₀, (colours matched to C). (C) Growth inhibitory response, determined from Incucyte analysis, of FaDu ATM KO cells to olaparib and AZD7648 treatment delivered by the Microformulator at fixed IC₉₀ and IC₅₀ concentrations for indicated durations throughout each 24-hour cycle over 3 weeks. Data represent mean ± SEM of 3 technical replicates. (D) FaDu ATM KO cells were treated for 24 hours with olaparib plus AZD7648 at either IC₅₀ or IC₉₀ and whole cell lysates were collected. Proteins were separated by SDS-PAGE and detected by western blotting. The band intensity of pDNA-PK S2056 was quantified and expression was normalised to the quantity of the respective total protein. Graphs represent mean expression ± SD for pDNA-PK relative to its expression in the DMSO control. Individual data points represent technical replicates. Underlying data can be found in S3 Data. DNA-PK, DNA-dependent protein kinase; KO, knockout; PK, pharmacokinetic.