Fig. 4: The YAP/TAZ transcriptional program is a prominent driver of KRAS G12C inhibitor resistance in lung cancer cells.
a, Sotorasib viability dose–response curves (means ± s.d.) for NCI-H358-P and NCI-H358-R cells (top) and NCI-H23-P and NCI-H23-R cells (bottom) (n = 3 independently treated cell cultures per condition). b, Western blot analysis showing KRAS G12C alkylation and target engagement and key pathway nodes in untreated parental cells versus NCI-H23-R and NCI-H358-R cells maintained in sotorasib. The experiments were repeated four times with consistent results. Vim., vimentin. c, Sotorasib viability dose–response curves (means ± s.d.) for parental NCI-H358-P cells and NCI-H358-R cells passaged in drug-free media for 8 weeks (NCI-H358-R released) (n = 3 independently treated cell cultures per condition) d, Chemical genetic screens of 720 small molecules, assessing differences in the mean viability values between sotorasib-resistant NCI-H358-R (left) and NCI-H23-R (right) cells versus their corresponding parental lines. The most enriched drug classes are shown, along with the median delta mean viability, normalized enrichment score (NES) and corresponding FDR value. The blue diamonds represent GNE-7883. e, Pathway enrichment for genes associated with upregulated ATAC-seq peaks in sotorasib-resistant NCI-H358-R (top) and NCI-H23-R (bottom) cells compared with parental cells under acute sotorasib treatment. Padj, adjusted P value. f, GSEA plot showing the enrichment of YAP/TAZ target genes among differentially expressed genes in sotorasib-resistant NCI-H358-R (top) and NCI-H23-R (bottom) cells and their corresponding parental cells under acute sotorasib treatment for 24 h. For d–f, the P values were calculated using GSEA and adjusted using Benjamini–Hochberg procedure.
