Fig. 1: Doses of trametinib that inhibit Ras/MEK/Erk signaling in vivo in mice without detrimental side effects.
a, Schematic outline of the trametinib pre-test experiment. Four-month-old C3B6 F1 hybrid mice were used for all experiments. b,c, Plasma concentration of trametinib in female (b) and male (c) mice (n = 5 plasma samples per treatment and sex, except n = 4 for male 0.29 mg kg−1) fed for 4 weeks with food containing 0, 0.29, 0.58, 1.44, 2.88 or 11.52 mg kg−1 trametinib. (One-way ANOVA with Bonferoniʼs post hoc test adjusted P values: female mice: 0 versus 11.52 P = 0.0073, 0.29 versus 11.52 P = 0.0077, 0.58 versus 11.52 P = 0.0082, 1.44 versus 11.52 P = 0.0116, 2.88 versus 11.52 P = 0.01; male mice: 0 versus 11.52 P < 0.0001, 0.29 versus 11.52 P < 0.0001, 0.58 versus 11.52 P < 0.0001, 1.44 versus 11.52 P < 0.0001, 2.88 versus 11.52 P < 0.0001). Female mice had significantly higher trametinib plasma levels than male mice across all doses, with a significant interaction of sex and drug (P = 0.0111, sex × drug, mixed model). d,e, Ras–Mek–Erk pathway activity in liver after 4 weeks of trametinib treatment, by western blot analysis of Erk1/2 phosphorylation. Representative western blot (upper panel) and corresponding quantification of female (d) and male (e) liver samples (n = 5 per treatment for both sexes). Trametinib concentrations of 1.44 mg kg−1 and higher inhibited Erk1/2 phosphorylation in liver of both sexes. f,g, Change in body weight upon 4 weeks of trametinib treatment in female (f) and male (g) mice. 11.52 mg kg−1 trametinib led to a significant reduction in body weight in both sexes compared to control animals (0 mg kg−1) (n = 5 animals per treatment). h,i, Wet spleen weight of female (h) and male (i) mice after 4 weeks of trametinib treatment. Spleen weight showed a tendency to increase with 11.52 mg kg−1 trametinib treatment. One-way ANOVA with Tukeyʼs post hoc test. Data are presented as mean ± s.e.m.
