Figure 2 from Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers

RMC-6236 inhibits RAS signaling and tumor growth and drives tumor regressions in vivo.A, Blood and tumor PK profiles of RMC-6236 in Capan-2 (KRASG12V/WT, PDAC) xenograft tumor-bearing BALB/c nude mice. Tumor-bearing mice were treated with a single dose of vehicle or RMC-6236 at 3, 10, or 25 mg/kg. Blood and tumors were harvested at indicated time points (n = 3/time point/dose). PK profiles are shown as RMC-6236 concentration in tumors (green lines) and blood (red lines) over time. Shades of green or red represent PK profiles at three tested doses. The dashed lines represent EC₅₀ and EC₉₀ potency of RMC-6236 in inhibiting DUSP6 mRNA expression in Capan-2 tumors derived from the PK/PD relationship curve in Fig. 5A. Values are plotted as mean ± SEM. B, PD of RMC-6236 in Capan-2 (KRASG12V/WT, PDAC) xenograft tumors, shown as the relative change in DUSP6 mRNA expression. Tumor-bearing mice were treated with a single dose (solid lines) of vehicle, RMC-6236 at 3, 10, or 25 mg/kg, or 7 consecutive daily doses of RMC-6236 at 25 mg/kg (dashed lines). Shades of green represent three tested doses. Solid lines represent a single dose while the dashed line represents repeat dosing. Values are plotted as mean ± SEM. C, Histopathology analysis of Capan-2 xenograft tumors treated with a single dose of vehicle control, or RMC-6236 at 3, 10, or 25 mg/kg or 7 consecutive daily doses of RMC-6236 at 25 mg/kg and collected at indicated time points (n = 2–3/time point/dose). pERK staining in tumor areas was quantified and compared with vehicle using one-way ANOVA followed by 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 group. Scale bar, 50 µm. D–G, Dose-dependent antitumor activity of RMC-6236 in subcutaneous xenograft models of (D) Capan-2 (KRASG12V/WT, PDAC; n = 8 per group), po qd, per os quaqua (once a day) (E) NCI-H441 (KRASG12V/WT, NSCLC; n = 10 per group), (F) HPAC (KRASG12D/WT, PDAC; n = 10 per group), and (G) NCI-H358 (KRASG12C/WT, NSCLC; n = 8–10 per group). Tumor-bearing mice were treated with vehicle or RMC-6236 at indicated doses for 27–28 days, and mean tumor volumes of each group were plotted over the course of treatment. Vehicle control and RMC-6236 groups were compared by two-way repeated-measures ANOVA on the last measurement day of the vehicle group (***, P < 0.001). The dotted line indicates the initial average tumor volume. Error bars, SEM. # indicates 1 animal terminated upon reaching a tumor burden endpoint.