title: INFERENCE OF PERSONALIZED DRUG TARGETS VIA NETWORK PROPAGATION.
abstract: We present a computational strategy to simulate drug treatment in a personalized setting. The method is based on integrating patient mutation and differential expression data with a protein-protein interaction network. We test the impact of in-silico deletions of different proteins on the flow of information in the network and use the results to infer potential drug targets. We apply our method to AML data from TCGA and validate the predicted drug targets using known targets. To benchmark our patient-specific approach, we compare the personalized setting predictions to those of the conventional setting. Our predicted drug targets are highly enriched with known targets from DrugBank and COSMIC (p < 10(-5) outperforming the non-personalized predictions. Finally, we focus on the largest AML patient subgroup (~30%) which is characterized by an FLT3 mutation, and utilize our prediction score to rank patient sensitivity to inhibition of each predicted target, reproducing previous findings of in-vitro experiments.
authors.affiliation: School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel†These authors contributed equally to this work., ortalits@gmail.com.
authors.forename: Ortal
authors.initials: O
authors.lastname: Shnaps
authors.forename: Eyal
authors.initials: E
authors.lastname: Perry
authors.forename: Dana
authors.initials: D
authors.lastname: Silverbush
authors.forename: Roded
authors.initials: R
authors.lastname: Sharan
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000494:pharmacology; D019295:Computational Biology / Q000379:methods / Q000706:statistics & numerical data; D003198:Computer Simulation; D062313:Databases, Pharmaceutical / Q000706:statistics & numerical data; D055808:Drug Discovery / Q000379:methods* / Q000706:statistics & numerical data; D053263:Gene Regulatory Networks; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D057285:Precision Medicine / Q000379:methods* / Q000706:statistics & numerical data; D060066:Protein Interaction Maps / Q000187:drug effects; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3