Figure 5. Prevention of BRaf^V600E-induced melanomas by PD325901.

(a) Adult Tyr::CreER; BRaf^CA/+; Pten^{lox4-5/lox4-5} mice were treated topically on the ear with 4-HT. One week later, mice were randomly assigned to be administered PD325901 (12.5mg/kg, n=12) or the solvent control (n=12) for 6 weeks. Mice were analyzed daily for the presence of cutaneous malignant melanoma and euthanized according to a standard body conditioning score. After 6 weeks of PD325901 treatment 7 drug treated and 6 control mice were euthanized for analysis of skin sections. A further 5 PD325901 treated and 6 control mice were monitored over the course of a further 11 weeks without any further drug administration. These mice were analyzed for the presence of cutaneous malignant melanoma as described above. Mouse survival was plotted using a Kaplan-Meier survival curve (c).

(b) Representative anatomical and histological images of skin from 4-HT treated Tyr::CreER; BRaf^CA/+; Pten^{lox4-5/lox4-5} mice analyzed after 6 weeks of treatment with control solvent (n=6, i) or PD325910 (n=7, ii) or from PD325901 treated mice left without further drug administration for an additional 9-11 weeks (iii).

(c) Kaplan-Meier survival curve of vehicle (n=6) or PD325901 (n=5) treated cohorts of mice analyzed in this experiment. All mice were treated for the indicated 6 weeks as in (b). Log rank tests of survival plots of the data demonstrate a statistically significant difference between vehicle and PD325901 treated animals (p=0.0024).

(d) 3 week old Tyr::CreER; BRaf^CA/+; Pten^{lox4-5/lox4-5} mice (n=10) were treated topically on the right ear with 4-HT. 10 days later all mice were administered PD325901 (12.5mg/kg) for 6 weeks. Drug administration was then ceased for 8 weeks. Mice were then randomized into two groups: Group A (blue) was administered vehicle control and Group B (red) was administered PD325901 for a further 6 weeks. At the end of this period mice were monitored prospectively for disease progression as described above. Mouse survival was plotted using a Kaplan-Meier survival curve that demonstrated statistically significant difference (p=0.0018) between the groups by log rank tests (e).