Fig. 3: Identification and validation of cell line–gene–drug interactions.

a Heat maps displaying the relative cell number for each cell line-sgRNA pair 72 h after treatment with 4-Hydroxytamoxifen (4-OHT), Lapatinib, or YM155 as measured using QMAP-Seq. Data are represented as mean of two biologically independent replicates. Asterisks denote positive controls. b Scatterplot of the dose–response curve AUC as determined using QMAP-Seq with one cell line versus QMAP-Seq with multiple cell lines. Common compounds for MDA-MB-231 cells are shown. Statistical significance of Pearson correlation was determined using a two-tailed test (n = 220 compound-sgRNA combinations). c Volcano plot depicting cell line–gene–drug interactions. Magnitude was determined by calculating the difference in mean AUC between sgRNA and sgNT for every cell line-compound combination. Statistical significance was determined using an unpaired, two-tailed t test (n = 2 biologically independent replicates). Blue dots indicate interactions where the knockout confers greater sensitivity than sgNT. Red dots indicate interactions where the knockout confers greater resistance than sgNT. d Pathways targeted by compounds involved in the top 60 sensitivity interactions (blue circles) or top 124 resistance interactions (red circles) that were significantly enriched compared to expected pathway representation. Statistical significance of pathway enrichment was determined using a one-tailed binomial test to compare observed distribution with expected distribution (n = 180 compounds). e List of the top 12 conditions that confer compound sensitivity or resistance. f Top: Dose–response curves for four of the top chemical–genetic interactions as measured using QMAP-Seq. Each data point represents one of two biologically independent replicates. Bottom: Dose–response curves as measured using Resazurin Cell Viability Kit. Each data point represents one of three biologically independent replicates. For clarity, individual proteostasis factor knockout curves are partioned across four panels; sgNT is same in all cases.