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. 2023 Nov 22;30(3):586–599. doi: 10.1158/1078-0432.CCR-23-0163

Figure 4.

Figure 4. Resistance to type II JAK inhibition is overcome in vivo by combined JAK2/AXL inhibition. A, JAK2 inhibitor resistant SET2 cells (JAKi-R) were injected subcutaneously into the flank of NSG mice. Animals were treated orally with type II JAK2 inhibitor CHZ868 15 mg/kg every day, AXL inhibitor bemcentinib (bem) 50 mg/kg twice a day, combined CHZ868 15 mg/kg every day/bemcentinib 50 mg/kg twice a day or vehicle control. Treatment was initiated at 100 mm3 tumor size and continued until maximal tumor size was reached in vehicle treated mice. B, Analysis of tumor weight at end of treatment confirmed significant reduction of tumor growth in vivo by AXL inhibition with bemcentinib or by combined JAK2/AXL inhibition with CHZ868/bemcentinib (n = 6/group). C, Tumor size over time showed tumor growth in vehicle-treated mice and analogously in CHZ868-treated mice suggesting resistance to type II JAK2 inhibition in vivo. AXL inhibition by bemcentinib significantly reduced tumor growth, while combined JAK2/AXL inhibition almost suppressed tumor growth (n = 6/group). D, Photographic image of isolated tumors at end of treatment. E, Tumor growth in individual mice is shown for each treatment group. Black lines indicate the average tumor size per group. Combined CHZ868/bemcentinib almost suppressed tumor growth in all the treated mice. Data are presented as mean ± SD and analyzed by one-way ANOVA. ns, not significant; *, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.001; ****, P ≤ 0.0001.

Resistance to type II JAK inhibition is overcome in vivo by combined JAK2/AXL inhibition. A, JAK2 inhibitor resistant SET2 cells (JAKi-R) were injected subcutaneously into the flank of NSG mice. Animals were treated orally with type II JAK2 inhibitor CHZ868 15 mg/kg every day, AXL inhibitor bemcentinib (bem) 50 mg/kg twice a day, combined CHZ868 15 mg/kg every day/bemcentinib 50 mg/kg twice a day or vehicle control. Treatment was initiated at 100 mm3 tumor size and continued until maximal tumor size was reached in vehicle treated mice. B, Analysis of tumor weight at end of treatment confirmed significant reduction of tumor growth in vivo by AXL inhibition with bemcentinib or by combined JAK2/AXL inhibition with CHZ868/bemcentinib (n = 6/group). C, Tumor size over time showed tumor growth in vehicle-treated mice and analogously in CHZ868-treated mice suggesting resistance to type II JAK2 inhibition in vivo. AXL inhibition by bemcentinib significantly reduced tumor growth, while combined JAK2/AXL inhibition almost suppressed tumor growth (n = 6/group). D, Photographic image of isolated tumors at end of treatment. E, Tumor growth in individual mice is shown for each treatment group. Black lines indicate the average tumor size per group. Combined CHZ868/bemcentinib almost suppressed tumor growth in all the treated mice. Data are presented as mean ± SD and analyzed by one-way ANOVA. ns, not significant; *, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.001; ****, P ≤ 0.0001.