title: Early spatiotemporal-specific changes in intermediate signals are predictive of cytotoxic sensitivity to TNFα and co-treatments.
abstract: Signaling pathways can generate different cellular responses to the same cytotoxic agents. Current quantitative models for predicting these differential responses are usually based on large numbers of intracellular gene products or signals at different levels of signaling cascades. Here, we report a study to predict cellular sensitivity to tumor necrosis factor alpha (TNFα) using high-throughput cellular imaging and machine-learning methods. We measured and compared 1170 protein phosphorylation events in a panel of human lung cancer cell lines based on different signals, subcellular regions, and time points within one hour of TNFα treatment. We found that two spatiotemporal-specific changes in an intermediate signaling protein, p90 ribosomal S6 kinase (RSK), are sufficient to predict the TNFα sensitivity of these cell lines. Our models could also predict the combined effects of TNFα and other kinase inhibitors, many of which are not known to target RSK directly. Therefore, early spatiotemporal-specific changes in intermediate signals are sufficient to represent the complex cellular responses to these perturbations. Our study provides a general framework for the development of rapid, signaling-based cytotoxicity screens that may be used to predict cellular sensitivity to a cytotoxic agent, or identify co-treatments that may sensitize or desensitize cells to the agent.
authors.affiliation: Bioinformatics Institute, Agency for Science, Technology and Research, 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore.
authors.forename: Lit-Hsin
authors.initials: LH
authors.lastname: Loo
authors.affiliation: Bioinformatics Institute, Agency for Science, Technology and Research, 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore.
authors.forename: Nicola Michelle
authors.initials: NM
authors.lastname: Bougen-Zhukov
authors.affiliation: Bioinformatics Institute, Agency for Science, Technology and Research, 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore.
authors.forename: Wei-Ling Cecilia
authors.initials: WC
authors.lastname: Tan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha