Fig. 7: Combination of JAK2 and MEK inhibition showed improved efficacy in CBFA2T3::GLIS2 NRAS-mutant PDX cells.
From: Identifying targeted therapies for CBFA2T3::GLIS2 acute myeloid leukemia
A. Combination index vs. fractional inhibition dotplot for the combination of ruxolitinib and trametinib in CPCT-0027 after 5 days of treatment. Normalized isobologram depicts CI scores over a range of concentrations. The coordinates of the CI scores are d1/Dx1 and d2/Dx2, where Dx1 is the concentration of drug 1 (ruxolitinib) that alone produces the fractional inhibition effect x, and Dx2 is the concentration of drug 2 (trametinib) that alone produces the fractional inhibition effect x. The red line displayed is the line of additivity. Points below the line are synergistic, and above the line are antagonistic. B Combination index vs. fractional inhibition dotplot for the combination of ruxolitinib and selumetinib in CPCT-0027 after 5 days of treatment. Normalized isobologram depicts CI scores over a range of concentrations, with drug 1 (ruxolitinib) and drug 2 (selumetinib). Log10(CI) intervals for: Strong Synergy: ≤−0.22, Synergy: > −0.22, ≤−0.10, Additivity: > −0.10, <0.08, Antagonism: ≥0.08, <0.20, Strong Antagonism: ≥0.20. C Quantification of percentage of hCD45 positive cells in the bone marrow and spleen in the CPCT-0027 model in vivo after 10 days of treatment. *P < 0.05 using one-way ANOVA with Tukey’s multiple comparisons test. D Kaplan–Meier survival curve for CPCT-0027 mice treated with vehicle, ruxolitinib (60 mg/kg PO BID), selumetinib (50 mg/kg PO BID) or the combination of ruxolitinib and selumetinib. N = 7/group. **P < 0.01; *P < 0.05; ns not significant using Log-rank test. E Median fluorescence intensity for pERK expression in the peripheral blood of mice treated with vehicle, selumetinib, ruxolitinib or the combination after 10 days of treatment. ****P < 0.0001 using one-way ANOVA with Tukey’s multiple comparisons test. F Median fluorescence intensity for pSTAT5 expression in peripheral blood after 10 days of treatment. **P < 0.01; *P < 0.05 using one-way ANOVA with Tukey’s multiple comparisons test.
