Fig. 3: MTX-531 inhibits EGFR and PI3K–mTOR signaling and tumor growth in HNSCC PDX models.
a, Pharmacodynamic modulation of EGFR and PI3K–mTOR pathway expression in NCI 848979-319-R xenografts 2 h after a single oral dose of 100 mg kg−1 MTX-531 (n = 5 mice per group) followed by immunoblot analysis and quantification by densitometry (right). Data are presented as the mean values ± s.e.m. and are representative of two individual experiments. b, Tumor growth inhibition after oral daily administration of 100 mg kg−1 MTX-531 to mice implanted with PIK3CA-mutant HNSCC PDX models NCI 245127-232-R (n = 6 mice per group), NCI 354836-022-R (n = 5 mice per group), NCI 455876-151-R (n = 8 mice per group), NCI 848979-319-R (n = 8 mice per group) and NCI 944545-341-R (n = 6 mice per group). Data are shown as the mean tumor volume ± s.e.m. Statistical differences in tumor growth rates for MTX-531 versus vehicle treatment were determined using a linear mixed model (Extended Data Fig. 4c). c, Waterfall plot of the best individual response of mice treated with MTX-531 in b. The percentage increase in tumor burden observed in the vehicle-treated mice ranged between 773% and 912% across models. d, Left, extension in survival of NCI 944545-341-R tumor-bearing mice (n = 6 mice per group). Mice were treated with MTX-531 (100 mg kg−1 PO) daily for 155 days or until tumor burden reached 1,000 mm³. Statistical differences in survival between the two arms was determined using the log-rank (Mantel–Cox) test. Right, plot depicting the duration of treatment required to elicit objective responses in individual mice. e, Antitumor efficacy of MTX-531 versus combination of erlotinib and alpelisib against NCI 944545-341-R xenografts. Mice (n = 8 mice per group) were treated daily for 14 days at the indicated doses. Data are shown as the mean change in tumor volume ± s.e.m. (left) and the mean change in tumor volume over time (middle). Statistical significance was determined by a one-way ANOVA comparison among all groups. Right, the effects of treatment on body weight change ± s.e.m. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 and ****P ≤ 0.0001.
