title: DIFFERENTIAL PATHWAY DEPENDENCY DISCOVERY ASSOCIATED WITH DRUG RESPONSE ACROSS CANCER CELL LINES.
abstract: The effort to personalize treatment plans for cancer patients involves the identification of drug treatments that can effectively target the disease while minimizing the likelihood of adverse reactions. In this study, the gene-expression profile of 810 cancer cell lines and their response data to 368 small molecules from the Cancer Therapeutics Research Portal (CTRP) are analyzed to identify pathways with significant rewiring between genes, or differential gene dependency, between sensitive and non-sensitive cell lines. Identified pathways and their corresponding differential dependency networks are further analyzed to discover essentiality and specificity mediators of cell line response to drugs/compounds. For analysis we use the previously published method EDDY (Evaluation of Differential DependencY). EDDY first constructs likelihood distributions of gene-dependency networks, aided by known genegene interaction, for two given conditions, for example, sensitive cell lines vs. non-sensitive cell lines. These sets of networks yield a divergence value between two distributions of network likelihoods that can be assessed for significance using permutation tests. Resulting differential dependency networks are then further analyzed to identify genes, termed mediators, which may play important roles in biological signaling in certain cell lines that are sensitive or non-sensitive to the drugs. Establishing statistical correspondence between compounds and mediators can improve understanding of known gene dependencies associated with drug response while also discovering new dependencies. Millions of compute hours resulted in thousands of these statistical discoveries. EDDY identified 8,811 statistically significant pathways leading to 26,822 compound-pathway-mediator triplets. By incorporating STITCH and STRING databases, we could construct evidence networks for 14,415 compound-pathway-mediator triplets for support. The results of this analysis are presented in a searchable website to aid researchers in studying potential molecular mechanisms underlying cells' drug response as well as in designing experiments for the purpose of personalized treatment regimens.
authors.affiliation: The Translational Genomics Research Institute, Phoenix, AZ 85004, U.S.A., gspeyer@tgen.org.
authors.forename: Gil
authors.initials: G
authors.lastname: Speyer
authors.forename: Divya
authors.initials: D
authors.lastname: Mahendra
authors.forename: Hai J
authors.initials: HJ
authors.lastname: Tran
authors.forename: Jeff
authors.initials: J
authors.lastname: Kiefer
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.forename: Harshil
authors.initials: H
authors.lastname: Dhruv
authors.forename: Michael
authors.initials: M
authors.lastname: Berens
authors.forename: Seungchan
authors.initials: S
authors.lastname: Kim
mesh_terms: D000465:Algorithms; D045744:Cell Line, Tumor; D019295:Computational Biology; D064550:Death-Associated Protein Kinases / Q000037:antagonists & inhibitors; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D057166:High-Throughput Screening Assays; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D057285:Precision Medicine; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D064550:Death-Associated Protein Kinases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D013449:Sulfonamides; C497442:HIF1A protein, human; C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; C528327:fedratinib; D000096926:Benzenesulfonamides; C579101:DAPK3 protein, human