title: Systematic drug screening reveals specific vulnerabilities and co-resistance patterns in endocrine-resistant breast cancer.
abstract: The estrogen receptor (ER) inhibitor tamoxifen reduces breast cancer mortality by 31 % and has served as the standard treatment for ER-positive breast cancers for decades. However, 50 % of advanced ER-positive cancers display de novo resistance to tamoxifen, and acquired resistance evolves in 40 % of patients who initially respond. Mechanisms underlying resistance development remain poorly understood and new therapeutic opportunities are urgently needed. Here, we report the generation and characterization of seven tamoxifen-resistant breast cancer cell lines from four parental strains.
  
  
  
  Using high throughput drug sensitivity and resistance testing (DSRT) with 279 approved and investigational oncology drugs, exome-sequencing and network analysis, we for the first time, systematically determine the drug response profiles specific to tamoxifen resistance.
  
  
  
  We discovered emerging vulnerabilities towards specific drugs, such as ERK1/2-, proteasome- and BCL-family inhibitors as the cells became tamoxifen-resistant. Co-resistance to other drugs such as the survivin inhibitor YM155 and the chemotherapeutic agent paclitaxel also occurred.
  
  
  
  This study indicates that multiple molecular mechanisms dictate endocrine resistance, resulting in unexpected vulnerabilities to initially ineffective drugs, as well as in emerging co-resistances. Thus, combatting drug-resistant tumors will require patient-tailored strategies in order to identify new drug vulnerabilities, and to understand the associated co-resistance patterns.
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Biomedicum 2U, Tukholmankatu 8, 00290, Helsinki, Finland. sara.kangaspeska@helsinki.fi.|Present address: Helsinki Innovation Services, Tukholmankatu 8 A, 00290, Helsinki, Finland. sara.kangaspeska@helsinki.fi.
authors.forename: Sara
authors.initials: S
authors.lastname: Kangaspeska
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Biomedicum 2U, Tukholmankatu 8, 00290, Helsinki, Finland.
authors.forename: Susanne
authors.initials: S
authors.lastname: Hultsch
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Biomedicum 2U, Tukholmankatu 8, 00290, Helsinki, Finland.
authors.forename: Alok
authors.initials: A
authors.lastname: Jaiswal
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Biomedicum 2U, Tukholmankatu 8, 00290, Helsinki, Finland.|Present address: MediSapiens Ltd, Erottajankatu 19B, 00130, Helsinki, Finland.
authors.forename: Henrik
authors.initials: H
authors.lastname: Edgren
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Biomedicum 2U, Tukholmankatu 8, 00290, Helsinki, Finland.
authors.forename: John-Patrick
authors.initials: JP
authors.lastname: Mpindi
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Biomedicum 2U, Tukholmankatu 8, 00290, Helsinki, Finland.
authors.forename: Samuli
authors.initials: S
authors.lastname: Eldfors
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Biomedicum 2U, Tukholmankatu 8, 00290, Helsinki, Finland.
authors.forename: Oscar
authors.initials: O
authors.lastname: Brück
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Biomedicum 2U, Tukholmankatu 8, 00290, Helsinki, Finland.
authors.forename: Tero
authors.initials: T
authors.lastname: Aittokallio
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Biomedicum 2U, Tukholmankatu 8, 00290, Helsinki, Finland.|Present address: Science for Life Laboratory, Department Oncology-Pathology, Karolinska Institutet, Tomtebodavägen 23, 171 65, Solna, Sweden.
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D015507:Drugs, Investigational; D059472:Exome; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects*; D042822:Genomic Instability; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D061986:MCF-7 Cells; D009285:Naphthoquinones / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D017422:Sequence Analysis, DNA / Q000379:methods; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D015507:Drugs, Investigational; D007093:Imidazoles; D009285:Naphthoquinones; D054852:Small Molecule Libraries; D013629:Tamoxifen; D017239:Paclitaxel; C523798:sepantronium
keywords: Breast cancer; Drug resistance; Exome-sequencing; High-throughput drug testing; Tamoxifen resistance