title: Construction of signaling pathways and identification of drug effects on the liver cancer cell HepG2.
abstract: Construction of signaling pathway maps and identification of drug effects are major challenge for pharmaceutical industries. Signaling maps are usually obtained from manual literature search, automated text mining algorithms, or canonical pathway databases (i.e. Reactome, KEGG, STKE, Pathway Studio, Ingenuity etc.) and in some cases they are used in combination with gene expression or mass spec data in an effort to create pathways specific to cell types or diseases. Our approach combines computational models with novel multicombinatorial high-throughput phosphoproteomic data for the functional analysis of signalling networks in mammalian cells. On the experimental front, we subject the cells with hundreds of co-treatment with a diverse set of ligands and inhibitors and we measure phosphorylation events on key signaling proteins using the xMAP technology. On the computational front, we create pathway maps that are cell type specific by fitting our phosphoprotein dataset into generic signaling maps via an Integer Linear programming formulation. To identify drug effects, we monitor the differences of topologies created with and without the presence of drug. In the present work, we use this approach to identify the effects of Nilotinib, a well known anti-cancer drug.
authors.affiliation: Department of Mechanical Engineering of National Technical University of Athens, 15780 Greece.
authors.forename: Leonidas G
authors.initials: LG
authors.lastname: Alexopoulos
authors.forename: Ioannis N
authors.initials: IN
authors.lastname: Melas
authors.forename: Aikaterini D
authors.initials: AD
authors.lastname: Chairakaki
authors.forename: Julio
authors.initials: J
authors.lastname: Saez-Rodriguez
authors.forename: Alexander
authors.initials: A
authors.lastname: Mitsos
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019295:Computational Biology / Q000379:methods*; D057225:Data Mining; D056945:Hep G2 Cells; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; C498826:nilotinib