Figure 4.

A multiple-low-dose drug combination is anti-proliferative in OCMs. (A) The two-stage strategy for the MLD screen. In Stage 1, the time-lapse microscopy drug-sensitivity profiling in Figure 3 was used to determine the GI₁₀ dose of the 16 OCMs and FNE1 cell line to PARGi, ATRi, CHK1i and WEE1i. In Stage 2, all possible two-, three- and four-drug combinations were evaluated in the proliferation assay using the GI₁₀ doses for each OCM and FNE1 cells defined in Stage 1. (B) The 16 OCMs and FNE1 cells were treated with the drug combinations indicated at the GI₁₀ doses for 96 h. For each MLD regimen the AUC of the proliferation curve was measured and normalized to that of untreated cells and summarized as % in a heatmap. For OCMs where a GI₁₀ could not be determined, a generic low dose was used (i.e. PARGi = 100 nM, ATRi = 2 μM). Data are from three technical replicates. (C) Comparison of the normalized AUC of ATRi-CHK1i and CHK1i-WEE1i low-dose combinations for each OCM. Note, OCM.109 is excluded as an GI₁₀ dose to ATRi was not calculable. Pearson's r is used to measure correlation. Two-tailed P value, ** P ≤ 0.01. See also Figure 3 and Supplementary Figure S4.