Extended Data Fig. 9: Cetuximab combination augments MRTX1133-mediated inhibition of KRAS signaling and tumor growth.
From: Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor
(a) Tumor growth inhibition following treatment with MRTX1133, cetuximab, or the combination administered i.p. to mice bearing the LS180 cell line xenograft (n = 5/group). Data are shown as mean tumor volume+/− SEM. Tumor volumes for the combination group were statistically significant vs all single agent treatment groups by a two-tailed Student’s t-test (* = p-value <0.05, ** = p-value <0.001) and body weight loss was <15% for the duration of the study in all groups. (b) Tumor growth inhibition following treatment with MRTX1133, cetuximab, or the combination administered i.p. to mice bearing the SW1990, Panc 02.03, Panc 04.03, or SNU-1033 cell line xenograft (n = 5/group). Data are shown as mean tumor volume+/− SEM. Tumor volumes for the combination group were statistically significant vs all single agent treatment groups by a two-tailed Student’s t-test (* = p-value <0.05, ** = p-value <0.001). Body weight loss was <15% for the duration of the study in all groups. (c) Immunohistochemical staining for pERK from mice administered MRTX1133 BID, cetuximab, or the combination followed by tumor harvest at 6 and 24 hours post dose, or MRTX1133 dosed BID for 7 days, cetuximab at 0.25 mg/dose Q3D, or the combination administered i.p. to mice bearing the AsPC-1 cell line xenograft (n = 3/time point). Images are at 10x magnification and representative of the treatment group, scale 200um. (d) Immunohistochemical staining for pS6 from mice dosed with MRTX1133 BID, cetuximab, or the combination followed by tumor harvest at 6 and 24 hours post dose, or MRTX1133 dosed BID for 7 days, cetuximab at 0.25 mg/dose Q3D, or the combination administered i.p. to mice bearing the AsPC-1 cell line xenograft (n = 3/time point). Images are at 10x magnification and representative of the treatment group, scale 200um.. (e) Percent of tumor cells positive for pERK assessed via immunohistochemistry from mice bearing the LS180 cell line xenograft dosed with MRTX1133 BID, cetuximab, or the combination followed by tumor harvest at 6 and 24 hours post dose (n = 3/time point). Data are shown as mean+/− SD. (f) Body weights of xenograft-bearing mice on the treatment schedules shown (n = 5/group). Data are shown as mean body weights+/− SEM. In this study, GP2D cells were implanted into female NOD/SCID mice, and 2 out of the 5 animals dosed with MRTX1133 BID daily exhibited weight loss and required euthanasia. In all other studies, no appreciable body weight loss was observed with treatment. (g) Percent of tumor cells positive for Ki67 assessed via immunohistochemistry from mice bearing the AsPC-1 cell line xenograft dosed i.p. with MRTX1133, cetuximab, or the combination 24 hours after the second dose, or MRTX1133 dosed BID for 7 days, cetuximab dosed Q3D, or the combination (n = 3/time point) 24 hours after the last dose. Data are shown as mean+/− SD. Ki67 staining was statistically significant relative to vehicle using one-way ANOVA. ‘*’ indicate p-value <0.05. (h) Representative 10x immunohistochemistry images from study in G, representative of the treatment group, scale 200um.
