Figure 4.
In vivo assessment of optimal treatment regimen in a xenograft model
(A) Schematic representation of the treatment schedule applied in MiaPaCa-2 xenograft model. Cohort A: continuous treatment with SHP2i alone daily; cohort B: continuous treatment with ERKi alone daily; cohort C: continuous treatment with the combination of SHP2i and ERKi daily; cohort D: intermittent treatment with the combination of SHP2i and ERKi 5 days on/2 days off; cohort E: semi-continuous treatment schedule with daily dosing of SHP2i and intermittent dosing with ERKi 5 days on/2 days off; cohort F: continuous treatment with SHP2i and on alternate days with ERKi; cohort G: intermittent dosing with SHP2i alone 5 days on/2 days off; cohort H: intermittent dosing with ERKi alone 5 days on/2 days off; and cohort I: treatment with ERKi alone on alternate days. Control mice were continuously treated with vehicle. For all the xenograft experiments, 5 × 106 cells were subcutaneously injected into the right flank of NSG mice. When tumors reached 200–250 mm3, mice were randomly assigned into cohorts and treated by oral gavage with inhibitors or vehicle according to treatment schedule.
(B) Treatment response was assessed through tumor volume change using caliper measurements 3 times/week in MiaPaCa-2 (KRASG12C) xenograft model. Results represent mean ± SD.
(C) Tumor volume change at time point day 21(n = 15 for vehicle cohort, n = 16 for all other cohorts). The y axis shows tumor volume change in percentage from baseline. Each bar represents the difference in tumor volume in an individual animal. According to the RECIST criteria, black indicates progressive disease, dark gray indicates stable disease, and light gray indicates partial response. Vehicle and cohort C data from Figure 3 B are reported again for comparison. Significance was determined by one-way ANOVA with Bonferroni’s multiple comparison test.
See also Figure S2.