Figure 3. DCR-BCAT in combination with trametinib leads to synergistic efficacy in human CRC xenografts of varying genetic backgrounds.

A–C, Ls174t (A), LS411N (B) and SW403 (C) cells were implanted subcutaneously into the flank of nude mice. Animals were dosed with one of 6 different monotherapy or combination regimens as indicated (n=6/cohort) on the days shown by the arrows. For the combination regimens, subjects received both the DsiRNA (i.v.) first, immediately followed by trametinib (p.o.). Tumor volumes were measured frequently by caliper. Mean values are plotted, error bars represent the SEM. The percentages on the plots reflect the degree of tumor growth inhibition (TGI) at the time of the final measurement. P values and combination indices for synergy were determined as described in Materials and Methods. A, lower panel: parallel cohorts were necropsied 8 h after the last dose of the first cycle (Day 10). Tumor homogenates were subjected to western blots for phospho-ERK1/2 and total-ERK1/2. D, Immunohistochemistry for Ki67 for SW403 tumors. Ki67 staining was performed using FFPE tumor sections collected at the terminal time point (n=3), representative 10x images are shown. Scale bar = 600 μm. E, Quantitation of Ki67 mean intensity; each data point represents an individual animal.