title: Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells.
abstract: Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive type of cancer that lacks effective targeted therapy. Despite detailed molecular profiling, no targeted therapy has been established. Hence, with the aim of gaining deeper understanding of the functional differences of TNBC subtypes and how that may relate to potential novel therapeutic strategies, we studied comprehensive anticancer-agent responses among a panel of TNBC cell lines.
  
  
  
  The responses of 301 approved and investigational oncology compounds were measured in 16 TNBC cell lines applying a functional profiling approach. To go beyond the standard drug viability effect profiling, which has been used in most chemosensitivity studies, we utilized a multiplexed readout for both cell viability and cytotoxicity, allowing us to differentiate between cytostatic and cytotoxic responses.
  
  
  
  Our approach revealed that most single-agent anti-cancer compounds that showed activity for the viability readout had no or little cytotoxic effects. Major compound classes that exhibited this type of response included anti-mitotics, mTOR, CDK, and metabolic inhibitors, as well as many agents selectively inhibiting oncogene-activated pathways. However, within the broad viability-acting classes of compounds, there were often subsets of cell lines that responded by cell death, suggesting that these cells are particularly vulnerable to the tested substance. In those cases we could identify differential levels of protein markers associated with cytotoxic responses. For example, PAI-1, MAPK phosphatase and Notch-3 levels associated with cytotoxic responses to mitotic and proteasome inhibitors, suggesting that these might serve as markers of response also in clinical settings. Furthermore, the cytotoxicity readout highlighted selective synergistic and synthetic lethal drug combinations that were missed by the cell viability readouts. For instance, the MEK inhibitor trametinib synergized with PARP inhibitors. Similarly, combination of two non-cytotoxic compounds, the rapamycin analog everolimus and an ATP-competitive mTOR inhibitor dactolisib, showed synthetic lethality in several mTOR-addicted cell lines.
  
  
  
  Taken together, by studying the combination of cytotoxic and cytostatic drug responses, we identified a deeper spectrum of cellular responses both to single agents and combinations that may be highly relevant for identifying precision medicine approaches in TNBC as well as in other types of cancers.
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Prson
authors.initials: P
authors.lastname: Gautam
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Karhinen
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Szwajda
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Sawan Kumar
authors.initials: SK
authors.lastname: Jha
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Bhagwan
authors.initials: B
authors.lastname: Yadav
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Tero
authors.initials: T
authors.lastname: Aittokallio
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. krister.wennerberg@fimm.fi.
authors.forename: Krister
authors.initials: K
authors.lastname: Wennerberg
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D014408:Biomarkers, Tumor; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016000:Cluster Analysis; D019295:Computational Biology; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000072020:Synthetic Lethal Mutations / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D059467:Transcriptome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases
keywords: Antagonism; Chemosensitivity; Cytotoxicity; DSRT; DSS; Heterogeneity; Synergy; TNBC; Viability