To 1028 M). The number of samples in a cancer lineage screened for drug response is shown under the corresponding boxplot. Compounds denoted in blue text exhibited a broad array of responses in multiple cancer lineages and have been chosen for evaluation in this study, whereas compounds denoted in red text are examples of compounds excluded from evaluation. Cancer lineage abbreviations AU: autonomic; BO: bone; BR: breast; CN: central nervous method; EN: endometrial; HE: haematopoietic/lymphoid; KI: kidney; LA: big intestine; LI: liver; LU: lung; OE: oesophagus; OV: ovary; PA: pancreas; PL: pleura; SK: skin; SO: soft tissue; ST: stomach; TH: thyroid; UP: upper digestive; UR: urinary doi:ten.1371/journal.pone.0103050.gdisruption can reflect a genome instability phenotype that’s inherently resistant to genotoxic stress from chemotherapy [25,26]. In reality, our obtaining agrees with a recently reported DNA repair gene signature that was predictive of each homologous repair suppression contributing to genome instability as well as sensitivity to chemotherapy in patient research [27]. Enrichmentanalysis performed on the Irinotecan marker set revealed comparable dysregulated pathways associated with cell cycle handle and DNA harm repair (Table S6). This suggests these two mechanisms are normally vital for managing TOP1 inhibition. Because recurrent drug response pathways can be involved in only a subset of cancer varieties, we aimed to delineate the extent ofTable 1. Quantity of gene markers drastically correlated with response to distinctive drugs identified by PC-Meta, PC-Pool, and PCUnion approachespound Irinotecan Topotecan Panobinostat AZD6244 PD-Target(s) TOP1 TOP1 HDAC MEK MEKNo. of PC-Meta Markers 211 757 542 10No. of PC-Pool Markers (Overlap with PC-Meta) 832 (105; 13 ) 474 (256; 54 ) 723 (200; 28 ) 51 (6; 12 ) 46 (23; 50 )No. of PC-Union Markers (Overlap with PC-Meta) 30 (19; 63 ) 61 (57; 93 ) 58 (46; 79 ) 7 (1; 14 ) 156 (29; 19 )doi:ten.1371/journal.pone.0103050.tPLOS A single | www.plosone.orgCharacterizing Pan-Cancer Mechanisms of Drug SensitivityFigure 3. Top markers of response to TOP1 inhibitors: (A) SLFN11 and (B) HMGB2. Scatter plots show correlation amongst gene expression and pharmacological response values across several cancer lineages, exactly where up-regulation of SLFN11 and HMGB2 correlate with drug sensitivity (indicated by smaller IC50 values). doi:10.1371/journal.pone.0103050.gPLOS 1 | www.plosone.orgCharacterizing Pan-Cancer Mechanisms of Drug SensitivityPLOS One | www.Lumacaftor-d4 Isotope-Labeled Compounds plosone.orgCharacterizing Pan-Cancer Mechanisms of Drug SensitivityFigure four.Indolicidin web Pan-cancer analysis of TOP1 inhibitor Topotecan.PMID:23907521 (A) Pan-cancer pathways with significant involvement in drug response detected by PC-Meta, PC-Pool, PC-Union approaches (around the left). These pathways might be grouped into six biological processes (distinguished by background color), which converge on two distinct mechanisms. The involvement level of these pan-cancer pathways predicted by distinctive approaches is illustrated with blue horizontal bars. Pathway involvement in each cancer lineage predicted by PC-Meta is indicated by the intensity of red fills in corresponding table (on the ideal). Pan-cancer and lineage-specific pathway involvement (PI) scores are derived from pathway enrichment evaluation and calculated as -log10(BH-adjusted p-values). Only the best pathways with PI scores .1.three are shown. Cancer lineage abbreviations AU: autonomic; BO: bone; BR: breast; CN: central nervous technique; EN: endometrial.
