Fig. 5: GNE-7883 overcomes sotorasib resistance by suppressing the reactivation of YAP/TAZ target genes.
a, Heatmaps showing the efficacy (1 for maximum efficacy and 0 for no efficacy) across a dose–response matrix of GNE-7883 and sotorasib combination in NCI-H358 (left) and NCI-H23 (right) cells in 7 d viability assays. b, Schematic of the TraCe-seq setup to compare the response of NCI-H358 cells to sotorasib treatment alone versus in combination with GNE-7883. The bar graph shows the number of barcodes that were depleted versus survived after 2 months of sotorasib treatment. c, Uniform manifold approximation and projection visualization of all cells collected across all time points and conditions. d, Density plot visualization of the distribution of cells carrying either of the surviving barcodes across all time points and treatments. e, Plots showing the MAPK pathway (left) and YAP/TAZ target scores (right) for NCI-H358 cells belonging to different barcode categories (n = 82 distinct depleted barcodes and n = 2 distinct survived barcodes) at baseline (day 0) or under treatment. f, Comparison of the MAPK pathway (left) and YAP/TAZ target scores (right) for each NCI-H358 barcode category (n = 82 distinct depleted barcodes and n = 2 distinct survived barcodes) treated for 3 d with sotorasib alone or in combination with GNE-7883. For e and f, the boxes (for n > 3 only) represent the distribution of scores per barcode for all barcodes in a given category (the counts are aggregated based on the cell barcodes and the box plots comprise the pseudo-bulk values for barcodes in the different categories). The lower and upper hinges correspond to the first and third quartiles (that is, the 25th and 75th percentiles). The lower and upper whiskers extend from the hinge to the smallest or largest value no further than 1.5× the interquantile range from the hinge. The data beyond the ends of the whiskers are outlying points and have been plotted individually. P values were calculated by two-sided Wilcoxon rank-sum test. NS, not significant (P > 0.05). g–i, Fitted tumor volumes of the sotorasib-resistant NSCLC NCI-H358-R xenograft model (g; left; n = 7 mice per group) and sotorasib treatment-naive NSCLC NCI-H358-P xenograft model (g; right; n = 10 mice per group), NSCLC PDX LU11786 (h; left; n = 5 mice per group) and LU5268 models (h; right; n = 5 mice per group) and colorectal SW837 xenograft model (i; n = 10 mice per group) treated with sotorasib, GNE-7883 or both in combination.
