title: The DIONESUS algorithm provides scalable and accurate reconstruction of dynamic phosphoproteomic networks to reveal new drug targets.
abstract: Many drug candidates fail in clinical trials due to an incomplete understanding of how small-molecule perturbations affect cell phenotype. Cellular responses can be non-intuitive due to systems-level properties such as redundant pathways caused by co-activation of multiple receptor tyrosine kinases. We therefore created a scalable algorithm, DIONESUS, based on partial least squares regression with variable selection to reconstruct a cellular signaling network in a human carcinoma cell line driven by EGFR overexpression. We perturbed the cells with 26 diverse growth factors and/or small molecules chosen to activate or inhibit specific subsets of receptor tyrosine kinases. We then quantified the abundance of 60 phosphosites at four time points using a modified microwestern array, a high-confidence assay of protein abundance and modification. DIONESUS, after being validated using three in silico networks, was applied to connect perturbations, phosphorylation, and cell phenotype from the high-confidence, microwestern dataset. We identified enhancement of STAT1 activity as a potential strategy to treat EGFR-hyperactive cancers and PTEN as a target of the antioxidant, N-acetylcysteine. Quantification of the relationship between drug dosage and cell viability in a panel of triple-negative breast cancer cell lines validated proposed therapeutic strategies.
authors.affiliation: Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, USA. n-bagheri@northwestern.edu.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Ciaccio
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Chen
authors.forename: Richard B
authors.initials: RB
authors.lastname: Jones
authors.forename: Neda
authors.initials: N
authors.lastname: Bagheri
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015195:Drug Design; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D025941:Protein Interaction Mapping / Q000379:methods; D020543:Proteome / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012984:Software
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D020543:Proteome