Extended Data Fig. 3: NetBID identified LCK and related genes for association with dasatinib sensitivity in T-ALL.
a, Activity of each gene was inferred using NetBID as described in Method and then compared between dasatinib-sensitive vs –resistant T-ALL with P value listed in the far right column. Top panel describes the expression ranking of all genes from the most highly expressed in dasatinib-sensitive cases on the left to the most highly expressed in resistant T-ALL on the right. Each gene in this pathway regulates a multitude of targets and their expression is indicated in two rows with positive-regulated target genes on the top and negatively regulated target genes at the bottom. In the case of LCK, it has 188 positive and 147 negative targets, each represented by a vertical line. Red lines indicate high expression in dasatinib sensitive T-ALL and blue lines indicate high expression in dasatinib-resistant cases. P-value was estimated using two-tailed t test. b, NetBID results for dasatinib target genes for association with dasatinib sensitivity in T-ALL. Dasatinib target gene list is derived from three databases Drug Bank, DGIdb, and chemical proteomic-based TKI target profiling, as shown in the Venn diagram in the left panel. Thirteen targets are commonly identified across three sources. NetBID analysis identified four of these 13 targets with a significantly higher activity (LCK, SRC, FYN and FGR) in dasatinib-sensitive samples compared to resistant cases, with P value for the differential gene activity listed in the right panel. P-value was estimated using two-tailed t test. c, PTCRA and LCK activity were compared between dasatinib-sensitive vs -resistant T-ALL samples with RNA-seq data in the pharmacotyping cohort (N = 15 and 30, respectively), P-value was estimated using two-tailed t test. Boxplots show summary of data in terms of the minimum, maximum, sample median, and the first and third quartiles. d,e, Gene networks used to infer PTCRA (d) and LCK (e) activity in NetBID. Each spoke represents a target gene (positively-regulated as red and negatively regulated as blue), with gene name indicated at the edge of each arrow. P-value was estimated using two-tailed t test. f, Running NetBID analysis using only pediatric cases in the discovery cohort (N = 12 and 15 patients for dasatinib-sensitive and –resistant, respectively), we re-estimated Z score for each gene which were then correlated with those from NetBID analysis using all T-ALL cases. Genes in the 30 biomarker panel are labeled and P value was estimated using Pearson correlation test.
