Fig. 1. A CRISPR knockout library, targeted to druggable genes, is a viable strategy to prioritize potential synergies with commonly used chemotherapeutics.

a Simplified schematic of CRISPR-sensitizer screens (detailed schematic available in Supplementary Data Fig. 1a). b Summary of genomics features of cell lines used in the screen. “ADR” refers to predominantly adrenergic neuroblastoma cell lines and “MES” to predominantly mesenchymal cell lines^20,22,92. Mutation profiles were obtained from DepMap (details in Supplementary Data Table 2). c Volcano plot showing the log normalized gRNA fold change (LFC; x axis) and P-values (y axis) for each gene knockout in a CX-5461 vs DMSO control treated CHP-134 neuroblastoma cell line. Results were obtained using our 655 gene reduced representation library “SJ KnockOut nOn-Lethal (SKOOL)”. Positive controls, the known sensitizing knockouts (ATM and TOP1) are highlighted as red circles and known resistance knockouts (TOP2A and TOP2B) are highlighted as blue triangles (P-values calculate using MAGeCK). d Like (c) but for results obtained for the same genes using the genome-wide Brunello library. e–i Waterfall plots showing the gene rank for resistance of the direct drug protein targets in our dataset. Genes are ranked by the mean Z scores across all 18 cell lines of their RRA score for resistance. j Boxplot showing the median log₁₀ normalized gRNA read count from all screens in all cell lines (y axis) for n = 400 non-targeting (nt) control gRNAs (green box) and n = 326 gRNAs targeting 55 pan essential genes defined by DepMap (P-value from t-test). In all boxplots, the center line represents the median, the bound of box is upper and lower quartiles and whiskers are 1.5× the interquartile range. Source data are provided as a Source Data file.