Fig. 5: The combination of MTX-531 and sotorasib leads to regressions of KRASG12C-mutant CRC and pancreatic tumors.
a, Tumor growth inhibition was evaluated in response to treatment with MTX-531, sotorasib or their combination administered orally to mice bearing KRASG12C-mutant xenografts. Studies were carried out in CRC PDX models NCI 135848-042-T (left) and B8239 (middle) and the pancreatic MIA PaCa-2 model (right) (n = 5 mice per group). Top, data are shown as the mean tumor volume ± s.e.m. Bottom, 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 vehicle-treated mice was 434% (NCI 135848-042-T), 838% (B8239) and 970% (MIA PaCa-2). A linear mixed model fit was used to determine the statistical significance of tumor growth rate differences and a Wald test was used to determine significance between groups. *P ≤ 0.05, ***P ≤ 0.001 and ****P ≤ 0.0001). b, Top, therapeutic response of B8324 xenografts to treatment with MTX-531, sotorasib or their combination (n = 5 mice per group). B8324 is a KRASG12C-mutant CRC PDX model established after progression during clinical treatment with the combination of sotorasib and panitumumab. 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 vehicle-treated mice was 817%. A linear mixed model fit was used to determine the statistical significance of tumor growth rate differences and a Wald test was used to determine significance between different groups. ***P ≤ 0.001 and ****P ≤ 0.0001. Bottom left, pharmacodynamic modulation of EGFR and PI3K–mTOR pathway expression in B8324 xenografts. Tumors were excised 2 h after treatment with a single oral dose of 100 mg kg−1 MTX-531, 100 mg kg−1 sotorasib or their combination, followed by immunoblot analysis (n = 3 tumors per group) and quantification of kinase expression by densitometry. Bottom right, representative data are presented as the mean ± s.e.m. of two individual experiments.
