Fig. 7: Coordinated targeting of COX2 with BRAF + EGFR improves long-term efficacy in BRAFV600E CRC PDXs.
a,b, Tumor growth profiles in BRAFV600E CRC PDX models 1 and 2 treated with encorafenib (ENC) ± panitumumab ± celecoxib or vehicle (VEH; control). Changes in tumor volume relative to starting volume at day 1 (average ± standard error) are plotted over time. P values from two-sided Student’s t tests across all time points comparing treatment arms are shown as a grayscale underneath each graph. NS, not significant; X, not available. All raw and relative tumor volumes are available as Source Data. In a, n = 11 mice per treatment group; in b: VEH, n = 5 mice; ENC, n = 6 mice; ENC + PAN, n = 9 mice; ENC + PAN + CEL, n = 9 mice. c, GLMs to test the association of change in tumor volume over time, either between treatment arms and vehicle (left) or between combination therapy and encorafenib alone (right). A GLM was applied to each individual PDX model and to both PDXs combined. Top, effect size measured as the GLM standard coefficient comparing the efficacy of the treatment arms. Bottom, GLM FDR-corrected P values. d, Comparison of effect sizes and FDR-corrected P values of treatment arms with and without celecoxib, using vehicle or encorafenib treatment as the baseline (left and right, respectively). The same number of mice per group shown in a,b was used for the analyses in c,d. e, Mouse weight as a surrogate for treatment toxicity. Data are displayed as the average weight in grams ± s.d. All weights from the results shown in a,b were used: VEH, n = 16 mice; ENC, n = 17 mice; ENC + PAN, n = 20 mice; ENC + PAN + CEL, n = 20 mice. f, Schematic summary of the states of signaling pathways depending on treatment: (1) untreated tumors, with BRAF–MEK–ERK as the main driver of progression (red) and baseline activity of the EGFR and COX2–SRC signaling pathways (gray), and (2–4) tumors treated with drugs (listed on top) inhibiting the activity (blue) of the three distinct signaling axes: BRAF–MEK, EGFR and COX2–SRC–β-catenin In scenario (4), triple treatment collectively blocks the cooperative dependencies that drive resistance and progression.
