BH3 mimetics overcomes stromal protection to crizotinib in ALK+ ALCL cells. (A) Western blot analysis revealing the relative expression of the indicated (phospho)proteins in SUPM2 cells cultured alone or in the presence of MS-5 and treated with crizotinib (NT, 20-50-100 nM) for 72 hours. (B) Western blot analysis revealing the relative expression of the indicated (phospho)proteins in L82 cells cultured alone or in the presence of MS-5 and treated with crizotinib (NT, 20-50-100 nM) for 72 hours. (C) Bar plot reporting the percent viability assessed by propidium iodide (PI) incorporation in SUPM2 cells cultured alone or in the presence of MS-5 and treated with crizotinib (100 nM) and/or navitoclax (100 nM) for 72 hours. P values were estimated with 2-way ANOVA test using GraphPad software (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). (D) Bar plot reporting the percent viability assessed by PI incorporation in L82 cells cultured alone or in the presence of MS-5 and treated with crizotinib (150 nM) and/or navitoclax (100 nM) for 72 hours. P values were estimated with 2-way ANOVA test using GraphPad software (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). (E) Bar plot reporting the percent viability assessed by PI incorporation in SUPM2 cells cultured alone or in the presence of F103 cells and treated with crizotinib (100 nM) and/or navitoclax (100 nM) for 72 hours. P values were estimated with 2-way ANOVA test using GraphPad software (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). (F) Bar plot reporting the percent viability assessed by PI incorporation in L82 cells cultured alone or in the presence of F103 cells and treated with crizotinib (150 nM) and/or navitoclax (100 nM) for 72 hours. P values were estimated with 2-way ANOVA test using GraphPad software (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). (G) Bar plot reporting the percent viability assessed by PI incorporation in L82 cells cultured alone or in the presence of MS-5 and treated with crizotinib (150 nM) and/or venetoclax (200 nM) for 72 hours. P values were estimated with 2-way ANOVA test using GraphPad software (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). (H) Bar plot reporting the percent viability assessed by PI incorporation in IL-79 PDX-Dline cultured alone or in the presence of MS-5 and treated with crizotinib (50 nM) and/or venetoclax (200 nM) for 72 hours. P values were estimated with 2-way ANOVA test using GraphPad software (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). (I) Bar plot reporting the percent viability assessed by PI incorporation in SUPM2 cells cultured alone or in the presence of F72 and treated with crizotinib (100 nM) and/or venetoclax (200 nM) for 72 hours. P values were estimated with 2-way ANOVA test using GraphPad software (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). (J) Bar plot reporting the percent viability assessed by PI incorporation in DHL1 cells cultured alone or in the presence of HS-5 and treated with crizotinib (100 nM) and/or venetoclax (200 nM) for 72 hours. P values were estimated with 2-way ANOVA test using GraphPad software (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). (K) Antitumoral effect of crizotinib, venetoclax, or combinations in SUPM2 xenografts (6-12 xenografts per group). Error bars represent standard error of the mean (∗P < .05; ∗∗P < .001; ∗∗∗P < .001; ∗∗∗∗P < .0001). CTRL, control; ns, not significant.
Figure 7.

BH3 mimetics overcomes stromal protection to crizotinib in ALK+ ALCL cells. (A) Western blot analysis revealing the relative expression of the indicated (phospho)proteins in SUPM2 cells cultured alone or in the presence of MS-5 and treated with crizotinib (NT, 20-50-100 nM) for 72 hours. (B) Western blot analysis revealing the relative expression of the indicated (phospho)proteins in L82 cells cultured alone or in the presence of MS-5 and treated with crizotinib (NT, 20-50-100 nM) for 72 hours. (C) Bar plot reporting the percent viability assessed by propidium iodide (PI) incorporation in SUPM2 cells cultured alone or in the presence of MS-5 and treated with crizotinib (100 nM) and/or navitoclax (100 nM) for 72 hours. P values were estimated with 2-way ANOVA test using GraphPad software (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). (D) Bar plot reporting the percent viability assessed by PI incorporation in L82 cells cultured alone or in the presence of MS-5 and treated with crizotinib (150 nM) and/or navitoclax (100 nM) for 72 hours. P values were estimated with 2-way ANOVA test using GraphPad software (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). (E) Bar plot reporting the percent viability assessed by PI incorporation in SUPM2 cells cultured alone or in the presence of F103 cells and treated with crizotinib (100 nM) and/or navitoclax (100 nM) for 72 hours. P values were estimated with 2-way ANOVA test using GraphPad software (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). (F) Bar plot reporting the percent viability assessed by PI incorporation in L82 cells cultured alone or in the presence of F103 cells and treated with crizotinib (150 nM) and/or navitoclax (100 nM) for 72 hours. P values were estimated with 2-way ANOVA test using GraphPad software (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). (G) Bar plot reporting the percent viability assessed by PI incorporation in L82 cells cultured alone or in the presence of MS-5 and treated with crizotinib (150 nM) and/or venetoclax (200 nM) for 72 hours. P values were estimated with 2-way ANOVA test using GraphPad software (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). (H) Bar plot reporting the percent viability assessed by PI incorporation in IL-79 PDX-Dline cultured alone or in the presence of MS-5 and treated with crizotinib (50 nM) and/or venetoclax (200 nM) for 72 hours. P values were estimated with 2-way ANOVA test using GraphPad software (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). (I) Bar plot reporting the percent viability assessed by PI incorporation in SUPM2 cells cultured alone or in the presence of F72 and treated with crizotinib (100 nM) and/or venetoclax (200 nM) for 72 hours. P values were estimated with 2-way ANOVA test using GraphPad software (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). (J) Bar plot reporting the percent viability assessed by PI incorporation in DHL1 cells cultured alone or in the presence of HS-5 and treated with crizotinib (100 nM) and/or venetoclax (200 nM) for 72 hours. P values were estimated with 2-way ANOVA test using GraphPad software (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). (K) Antitumoral effect of crizotinib, venetoclax, or combinations in SUPM2 xenografts (6-12 xenografts per group). Error bars represent standard error of the mean (∗P < .05; ∗∗P < .001; ∗∗∗P < .001; ∗∗∗∗P < .0001). CTRL, control; ns, not significant.

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