title: Systematic Mapping of Kinase Addiction Combinations in Breast Cancer Cells by Integrating Drug Sensitivity and Selectivity Profiles.
abstract: Chemical perturbation screens offer the possibility to identify actionable sets of cancer-specific vulnerabilities. However, most inhibitors of kinases or other cancer targets result in polypharmacological effects, which complicate the identification of target dependencies directly from the drug-response phenotypes. In this study, we developed a chemical systems biology approach that integrates comprehensive drug sensitivity and selectivity profiling to provide functional insights into both single and multi-target oncogenic signal addictions. When applied to 21 breast cancer cell lines, perturbed with 40 kinase inhibitors, the subtype-specific addiction patterns clustered in agreement with patient-derived subtypes, while showing considerable variability between the heterogeneous breast cancers. Experimental validation of the top predictions revealed a number of co-dependencies between kinase targets that led to unexpected synergistic combinations between their inhibitors, such as dasatinib and axitinib in the triple-negative basal-like HCC1937 cell line.
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Szwajda
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Prson
authors.initials: P
authors.lastname: Gautam
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Karhinen
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Sawan Kumar
authors.initials: SK
authors.lastname: Jha
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Jani
authors.initials: J
authors.lastname: Saarela
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Sushil
authors.initials: S
authors.lastname: Shakyawar
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Turunen
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Bhagwan
authors.initials: B
authors.lastname: Yadav
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Jing
authors.initials: J
authors.lastname: Tang
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00014 Helsinki, Finland. Electronic address: krister.wennerberg@fimm.fi.
authors.forename: Krister
authors.initials: K
authors.lastname: Wennerberg
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00014 Helsinki, Finland. Electronic address: tero.aittokallio@fimm.fi.
authors.forename: Tero
authors.initials: T
authors.lastname: Aittokallio
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D049490:Systems Biology / Q000379:methods
chemical_list: D047428:Protein Kinase Inhibitors