TP53 loss impairs response to MCL1 BH3 mimetic S63845. (A) CRISPR/Cas9-mediated TP53 inactivation increased resistance to BH3 mimetic specific to MCL1. (Left) BH3 mimetic specific to MCL1 dose response in isogenic TP53^+/+ and TP53^−/− NCI-H929 and XG7 clones. Graphs represent 3 independent experiments. (Right) LD₅₀ S63845 values in TP53^+/+ control cells (bulk) and TP53^+/+ and TP53^−/− clones in NCI-H929 (top) and XG7 (bottom); see supplemental Table 7. Statistical analysis was performed using the Mann-Whitney U test. (B) CRISPR/Cas9-mediated TP53 inactivation decreased priming to MCL1. Priming to MCL1 was assessed by determining cytochrome-C release induced by MS1 peptide. Cytochrome-C staining was performed using anti–cytochrome-C monoclonal antibody and analyzed by flow cytometry. Graphs represent the mean ± standard deviation (SD) of 3 to 4 independent experiments. Statistical analysis was performed using the Wilcoxon matched pairs signed-rank test. (C) S63845 LD₅₀ values were significantly lower in TP53^wt HMCLs. S63845, venetoclax, and A1155463 LD₅₀ values were analyzed in 11 TP53^wt and 20 TP53^Abn HMCLs (supplemental Table 8). Each point represents 1 HMCL; median values are indicated. For A1155463 and venetoclax, LD₅₀ was arbitrarily set up at 20 000 and 10 000 nM when it did not reach 10 000 or 5000 nM, respectively. Statistical analyses were performed using the Mann-Whitney U test. ∗∗∗∗P < .0001; ∗∗∗P < .001; ∗∗P < .01; ∗P < .05.