Fig. 6

DMEA identifies selectively toxic MOAs based on external gene expression signatures of intrinsic EGFR inhibitor resistance and acquired RAF inhibitor resistance, respectively. Using gene expression signatures of intrinsic resistance to EGFR inhibition and acquired resistance to RAF inhibition, we calculated WGV molecular classification scores for 327 adherent cancer cell lines in the CCLE database. For each signature, the WGV scores were correlated with drug sensitivity scores (i.e., AUC) for 1351 drugs from the PRISM database. Drugs were then ranked by Pearson correlation coefficient, and DMEA was performed to identify selectively toxic MOAs. A DMEA analysis of GSE12790 [48] transcriptomic signature of intrinsic resistance to EGFR inhibitor erlotinib, including a volcano plot of NES versus − log₁₀(p value) for MOA evaluated where red text indicates MOAs with p value < 0.05 and FDR < 0.25 and a mountain plot showing that DMEA identified the EGFR inhibitor MOA as negatively enriched. The most negatively correlated EGFR inhibitors are labeled along with their correlation coefficients. B Comparison of three transcriptomic signatures for intrinsic resistance to EGFR inhibition analyzed using DMEA, including a Venn diagram showing the number of shared genes among the signatures and a dot plot illustrating the consistency of MOA enrichment across DMEA’s analyses. C DMEA analysis of GSE66539 [51] transcriptomic signature of acquired resistance to RAF inhibitor vemurafenib, including a volcano plot of NES versus − log₁₀(p value) for MOA evaluated where red text indicates MOAs with p value < 0.05 and FDR < 0.25 and a mountain plot showing that DMEA identified the RAF inhibitor MOA as negatively enriched. The most negatively correlated RAF inhibitors are labeled along with their correlation coefficients