Figure 5 from Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers

Effects of RMC-6236 mediated pharmacologic modulation of RAS pathway signaling in tumor-bearing mice. A, PK/PD relationship between RMC-6236 concentration and inhibition of DUSP6 expression in Capan-2 (EC₅₀ = 90 nmol/L and EC₉₀ = 809 nmol/L), NCI-H441 (EC₅₀ = 117 nmol/L and EC₉₀ = 1,121 nmol/L), and HPAC (EC₅₀ = 135 nmol/L and EC₉₀ = 925 nmol/L) xenograft tumors. Subcutaneous xenograft tumors were treated with vehicle or RMC-6236 ranging from 0.3 to 100 mg/kg (Capan-2 and H441) or to 50 mg/kg (HPAC). B, PK/PD relationship between RMC-6236 concentration and inhibition of Dusp6 expression in ear skin (EC₅₀ = 1,164 nmol/L and EC₉₀ = 10,279 nmol/L) isolated from tumor-bearing BALB/c nude mice treated with vehicle or RMC-6236 ranging from 3 mg/kg to 100 mg/kg. A and B, Tumors and ear skin from tumor-bearing BALB/c nude mice were harvested at indicated time points (n = 3/timepoint/dose). A 3-parameter sigmoidal exposure–response model was fitted to the data to derive EC₅₀ and EC₉₀ values. Time points are represented by colors and doses are represented by symbol shapes. C–G, Histopathology of tumors and ear skin from the Capan-2 xenograft model collected at indicated time points post a single dose of vehicle control, RMC-6236 at 25 mg/kg or 7 consecutive daily doses of RMC-6236 at 25 mg/kg (n = 3–6/time point/dose). Staining of indicated markers in the tumor area or ear skin was quantified and compared with vehicle using one-way ANOVA followed by the Dunnett multiple comparison test (*, P < 0.05; **, P < 0.01; ***, P < 0.001). Representative images are shown at 200× magnification from samples closest to the mean of the respective groups. Scale bar, 50 µm.