Fig. 4: Combination of MTX-531 with the MEK inhibitor trametinib leads to regressions in BRAF-mutant and KRAS-mutant CRC models.
Tumor growth inhibition after treatment with MTX-531, trametinib or their combination administered orally to mice bearing KRAS-A146T NCI CN0375-F725 PDX tumors (a; n = 5 mice per group) or BRAF-V600E UM-CRC 14-929 PDX tumors (b; n = 5 mice per group). Top left, data are shown as the mean tumor volume ± s.e.m. Top right, the best antitumor response seen in individual animals from each group is shown as a waterfall plot. The percentage increase in tumor burden observed in the vehicle-treated mice during these studies was 887% (NCI CN0375-F725) or 844% (UM-CRC 14-929). Bottom, the extension in survival conferred by each of the single agents and their combination. Effects of treatment on survival were quantified by euthanizing individual mice when the tumor burden reached 1000 mm3. Increase in lifespan (ILS) was determined from comparative survival of median animals in the treated versus control groups. A linear mixed model fit was used to determine the statistical significance of tumor growth rate differences and a Wald test was used for a significance test between the different groups. *P ≤ 0.05, ***P ≤ 0.001 and ****P ≤ 0.0001. Bottom right, pharmacodynamic modulation of EGFR and PI3K–mTOR pathway expression was evaluated in UM-CRC 14-929 xenografts. Mice were treated for 5 days at the same doses as studied in the efficacy experiment. Tumors were excised 2 h after the fifth treatment, followed by immunoblot analysis (n = 3 tumors per group). Data are representative of two individual experiments.
