In vitro response to BH3-mimetics in pediatric ALL xenografts. (A) Summary of the mean venetoclax LC50 at 48 hours of each xenograft determined by AlamarBlue assay. Data are segregated by venetoclax in vivo response. Bar represents the median LC50 of each cohort. Groups compared by Mann-Whitney test. (B) ALL xenografts cocultured with hTERT-MSCs were treated (concentration range 1 nM-4 μM) with navitoclax (n = 24), venetoclax (n = 24), A-1113567 (n = 23), or A-1155463 (n = 24) alone, or an equimolar 50:50 mixture of venetoclax and A-1155463 (n = 24). Viability was evaluated using propidium iodide exclusion by flow cytometry, and LC50s calculated by nonlinear regression in Graphpad Prism are summarized here. A range rather than scale is depicted for LC50 > 10 μM, as these correspond to extrapolated rather than measured values. Wilcoxon matched-pairs signed rank test was used for statistical comparison between groups. P values are represented as follows: *P ≤ .05; **P ≤ .01; ***P ≤ .001; ****P ≤ .0001. (C) Sensitivity to navitoclax correlates significantly with sensitivity to venetoclax alone or a 50:50 mixture of venetoclax and A-1155463, but not A-1155463 alone. A-1155463 LC50 could not be calculated for the 2 samples with the highest navitoclax LC50. Pearson correlation coefficients are listed. (D) Sensitivity to navitoclax, venetoclax, A-1113567, or A-1155463 alone, or the venetoclax and A-1155463 50:50 mixture, by ALL subtype. (E) In MLLr-ALL, sensitivity to navitoclax correlates strongly with venetoclax sensitivity.
