Figure 3.
Regression and sustained suppression of primary MPNSTs by dual inhibition of CDK4/6 and MEK in immune competent mice. (A) Schematic of the CRISPR-Cas9 targeting approach involving co-inactivation of Nf1, Ink4a and Arf in the sciatic nerve of wildtype C57BL/6N mice to generate de novo MPNSTs. Panels B-E: Once tumors reached ~250 mm3, mice were treated daily with vehicle (V), 100 mg/kg palbociclib (Palbo, P), 1 mg/kg mirdametinib (Mirda, M), or the combination (Combo, C). (B) Waterfall plot at day 10 showing tumor regression only in the combination treated mice. (C) Fold change in tumor volume over the treatment period. (D) Time (in days) for tumors to triple in size. (E) Survival of the treated mice (time to maximum 2000 mm3 tumor volume). Error bars, SEM. C: P value determined by a generalized linear model to assess the difference between the curves. B,D,E: P value, One-way ANOVA with Tukey’s correction (*, P < 0.05; ***, P < 0.001).