BH3 mimetics synergize with crizotinib in ALK+ ALCL. (A) Three-dimensional (3D) matrix plot revealing the effect of the drug combination (crizotinib plus navitoclax; synergism, additive effects or antagonism) in SUPM2 cells calculated and visualized using SynergyFinder plus software (highest single agent [HSA] reference model). Red regions, synergism; white, additive effect; green, antagonism. (B) 3D matrix plot revealing the effect of the drug combination (crizotinib plus navitoclax; synergism, additive effects or antagonism) in L82 cells calculated and visualized using SynergyFinder plus software (HSA reference model). Red regions, synergism; white, additive effect; green, antagonism. (C) 3D matrix plot revealing the effect of the drug combination (crizotinib plus navitoclax; synergism, additive effects or antagonism) in IL-69 PDX-Dline calculated and visualized using SynergyFinder plus software (has reference model). Red regions, synergism; white, additive effect; green, antagonism. (D) 3D matrix plot revealing the effect of the drug combination (crizotinib plus venetoclax; synergism, additive effects or antagonism) in SUPM2 cells calculated and visualized using SynergyFinder plus software (HSA reference model). Red regions, synergism; white, additive effect; green, antagonism. (E) 3D matrix plot revealing the effect of the drug combination (crizotinib plus venetoclax; synergism, additive effects, or antagonism) in IL-79 PDX-Dline calculated and visualized using SynergyFinder plus software (HSA reference model). Red regions, synergism; white, additive effect; green, antagonism. (F) Bar plot reporting the percent viability assessed by CellTiter-Glo assay of L82 cells transduced with BCL2 sh1 and treated for 72 hours with crizotinib (50 nM), in the presence or absence of doxycycline. 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 viability assessed by CellTiter-Glo assay of L82 cells transduced with BCL2 sh2 and treated for 72 hours with crizotinib (50 nM), in the presence or absence of doxycycline. P values were estimated with 2-way ANOVA test using GraphPad software (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). (H) Heat map reporting the percentage of PI+ cells of 9 PTCL PDX-Dlines treated for 72 hours with crizotinib and/or venetoclax at the indicated concentrations (y-axis). (I) Heat map reporting the percentage of PI+ cells of 9 PTCL PDX-Dlines treated for 72 hours with crizotinib and/or DT2216 at the indicated concentrations (y-axis). (J) 3D matrix plot revealing the effect of the drug combination (ruxolitinib plus navitoclax; synergism, additive effects, or antagonism) in MAC1 cells calculated and visualized using SynergyFinder plus software (has reference model). Red regions, synergism; white, additive effect; green, antagonism. (K) Synergy-sensitivity dot plot for all the drug combinations tested in ALCL cell lines and PDX-Dlines. HSA reference model. RUXO, ruxolitinib; VEN, venetoclax.
Figure 6.

BH3 mimetics synergize with crizotinib in ALK+ ALCL. (A) Three-dimensional (3D) matrix plot revealing the effect of the drug combination (crizotinib plus navitoclax; synergism, additive effects or antagonism) in SUPM2 cells calculated and visualized using SynergyFinder plus software (highest single agent [HSA] reference model). Red regions, synergism; white, additive effect; green, antagonism. (B) 3D matrix plot revealing the effect of the drug combination (crizotinib plus navitoclax; synergism, additive effects or antagonism) in L82 cells calculated and visualized using SynergyFinder plus software (HSA reference model). Red regions, synergism; white, additive effect; green, antagonism. (C) 3D matrix plot revealing the effect of the drug combination (crizotinib plus navitoclax; synergism, additive effects or antagonism) in IL-69 PDX-Dline calculated and visualized using SynergyFinder plus software (has reference model). Red regions, synergism; white, additive effect; green, antagonism. (D) 3D matrix plot revealing the effect of the drug combination (crizotinib plus venetoclax; synergism, additive effects or antagonism) in SUPM2 cells calculated and visualized using SynergyFinder plus software (HSA reference model). Red regions, synergism; white, additive effect; green, antagonism. (E) 3D matrix plot revealing the effect of the drug combination (crizotinib plus venetoclax; synergism, additive effects, or antagonism) in IL-79 PDX-Dline calculated and visualized using SynergyFinder plus software (HSA reference model). Red regions, synergism; white, additive effect; green, antagonism. (F) Bar plot reporting the percent viability assessed by CellTiter-Glo assay of L82 cells transduced with BCL2 sh1 and treated for 72 hours with crizotinib (50 nM), in the presence or absence of doxycycline. 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 viability assessed by CellTiter-Glo assay of L82 cells transduced with BCL2 sh2 and treated for 72 hours with crizotinib (50 nM), in the presence or absence of doxycycline. P values were estimated with 2-way ANOVA test using GraphPad software (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). (H) Heat map reporting the percentage of PI+ cells of 9 PTCL PDX-Dlines treated for 72 hours with crizotinib and/or venetoclax at the indicated concentrations (y-axis). (I) Heat map reporting the percentage of PI+ cells of 9 PTCL PDX-Dlines treated for 72 hours with crizotinib and/or DT2216 at the indicated concentrations (y-axis). (J) 3D matrix plot revealing the effect of the drug combination (ruxolitinib plus navitoclax; synergism, additive effects, or antagonism) in MAC1 cells calculated and visualized using SynergyFinder plus software (has reference model). Red regions, synergism; white, additive effect; green, antagonism. (K) Synergy-sensitivity dot plot for all the drug combinations tested in ALCL cell lines and PDX-Dlines. HSA reference model. RUXO, ruxolitinib; VEN, venetoclax.

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