Targeting PLK1 overcomes T-DM1 resistance via CDK1-dependent phosphorylation and inactivation of Bcl-2/xL in HER2-positive breast cancer View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2018-04

AUTHORS

Özge Saatci, Simone Borgoni, Özge Akbulut, Selvi Durmuş, Umar Raza, Erol Eyüpoğlu, Can Alkan, Aytekin Akyol, Özgür Kütük, Stefan Wiemann, Özgür Şahin

ABSTRACT

Trastuzumab-refractory, HER2 (human epidermal growth factor receptor 2)-positive breast cancer is commonly treated with trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the microtubule-targeting agent, DM1. However, drug response reduces greatly over time due to acquisition of resistance whose molecular mechanisms are mostly unknown. Here, we uncovered a novel mechanism of resistance against T-DM1 by combining whole transcriptome sequencing (RNA-Seq), proteomics and a targeted small interfering RNA (siRNA) sensitization screen for molecular level analysis of acquired and de novo T-DM1-resistant models of HER2-overexpressing breast cancer. We identified Polo-like kinase 1 (PLK1), a mitotic kinase, as a resistance mediator whose genomic as well as pharmacological inhibition restored drug sensitivity. Both acquired and de novo resistant models exhibited synergistic growth inhibition upon combination of T-DM1 with a selective PLK1 inhibitor, volasertib, at a wide concentration range of the two drugs. Mechanistically, T-DM1 sensitization upon PLK1 inhibition with volasertib was initiated by a spindle assembly checkpoint (SAC)-dependent mitotic arrest, leading to caspase activation, followed by DNA damage through CDK1-dependent phosphorylation and inactivation of Bcl-2/xL. Furthermore, we showed that Ser70 phosphorylation of Bcl-2 directly regulates apoptosis by disrupting the binding to and sequestration of the pro-apoptotic protein Bim. Importantly, T-DM1 resistance signature or PLK1 expression correlated with cell cycle progression and DNA repair, and predicted a lower sensitivity to taxane/trastuzumab combination in HER2-positive breast cancer patients. Finally, volasertib in combination with T-DM1 greatly synergized in models of T-DM1 resistance in terms of growth inhibition both in three dimensional (3D) cell culture and in vivo. Altogether, our results provide promising pre-clinical evidence for potential testing of T-DM1/volasertib combination in T-DM1 refractory HER2-positive breast cancer patients for whom there is currently no treatment available. More... »

PAGES

2251-2269

References to SciGraph publications

  • 2009-12. Modeling ERBB receptor-regulated G1/S transition to find novel targets for de novo trastuzumab resistance in BMC SYSTEMS BIOLOGY
  • 2015-01. T-DM1, a novel antibody-drug conjugate, is highly effective against uterine and ovarian carcinosarcomas overexpressing HER2 in CLINICAL & EXPERIMENTAL METASTASIS
  • 2005-10. On the road to cancer: aneuploidy and the mitotic checkpoint in NATURE REVIEWS CANCER
  • 2016-07. Prolonged mitotic arrest induces a caspase-dependent DNA damage response at telomeres that determines cell survival in SCIENTIFIC REPORTS
  • 2007-08. Rational combinations of siRNAs targeting Plk1 with breast cancer drugs in ONCOGENE
  • 2010-09. Mitochondria and cell death: outer membrane permeabilization and beyond in NATURE REVIEWS MOLECULAR CELL BIOLOGY
  • 2014-04. Trastuzumab emtansine: mechanisms of action and drug resistance in BREAST CANCER RESEARCH
  • 2004-06. Polo-like kinases and the orchestration of cell division in NATURE REVIEWS MOLECULAR CELL BIOLOGY
  • 2005-01. Differential regulation of polo-like kinase 1, 2, 3, and 4 gene expression in mammalian cells and tissues in ONCOGENE
  • 2007-10. Molecular heterogeneity of breast carcinomas and the cancer stem cell hypothesis in NATURE REVIEWS CANCER
  • 2007-04. Three-dimensional culture models of normal and malignant breast epithelial cells in NATURE METHODS
  • 2013-10. Modeling precision treatment of breast cancer in GENOME BIOLOGY
  • 2008-12. Self-regulated mechanism of Plk1 localization to kinetochores: lessons from the Plk1-PBIP1 interaction in CELL DIVISION
  • 2012-04. TP53 genomics predict higher clinical and pathologic tumor response in operable early-stage breast cancer treated with docetaxel-capecitabine ± trastuzumab in BREAST CANCER RESEARCH AND TREATMENT
  • 2012-07. Strong EGFR signaling in cell line models of ERBB2-amplified breast cancer attenuates response towards ERBB2-targeting drugs in ONCOGENESIS
  • 2016-10. miR-564 acts as a dual inhibitor of PI3K and MAPK signaling networks and inhibits proliferation and invasion in breast cancer in SCIENTIFIC REPORTS
  • 2011-04. Trastuzumab-DM1 causes tumour growth inhibition by mitotic catastrophe in trastuzumab-resistant breast cancer cells in vivo in BREAST CANCER RESEARCH
  • 2012-03-01. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks in NATURE PROTOCOLS
  • 2014-12. A pan-cancer proteomic perspective on The Cancer Genome Atlas in NATURE COMMUNICATIONS
  • 2014-07. Polo-like kinases: structural variations lead to multiple functions in NATURE REVIEWS MOLECULAR CELL BIOLOGY
  • 2005-04. Getting in and out of mitosis with Polo-like kinase-1 in ONCOGENE
  • 2012-05. Intra-tumour heterogeneity: a looking glass for cancer? in NATURE REVIEWS CANCER
  • 2016-11. The ErbB2ΔEx16 splice variant is a major oncogenic driver in breast cancer that promotes a pro-metastatic tumor microenvironment in ONCOGENE
  • 2007-05. The spindle-assembly checkpoint in space and time in NATURE REVIEWS MOLECULAR CELL BIOLOGY
  • 2012-03. Killing cells by targeting mitosis in CELL DEATH & DIFFERENTIATION
  • 2006-04. Targeting polo-like kinase 1 for cancer therapy in NATURE REVIEWS CANCER
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41388-017-0108-9

    DOI

    http://dx.doi.org/10.1038/s41388-017-0108-9

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1100749534

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29391599


    Indexing Status Check whether this publication has been indexed by Scopus and Web Of Science using the SN Indexing Status Tool
    Incoming Citations Browse incoming citations for this publication using opencitations.net

    JSON-LD is the canonical representation for SciGraph data.

    TIP: You can open this SciGraph record using an external JSON-LD service: JSON-LD Playground Google SDTT

    [
      {
        "@context": "https://springernature.github.io/scigraph/jsonld/sgcontext.json", 
        "about": [
          {
            "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/1112", 
            "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
            "name": "Oncology and Carcinogenesis", 
            "type": "DefinedTerm"
          }, 
          {
            "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/11", 
            "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
            "name": "Medical and Health Sciences", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Animals", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Breast Neoplasms", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "CDC2 Protein Kinase", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Cell Cycle Proteins", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Cell Line, Tumor", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Drug Resistance, Neoplasm", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Drug Synergism", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Female", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Humans", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Maytansine", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Mice", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Phosphorylation", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Protein-Serine-Threonine Kinases", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Proto-Oncogene Proteins", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Proto-Oncogene Proteins c-bcl-2", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Pteridines", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Receptor, ErbB-2", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Signal Transduction", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Trastuzumab", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Xenograft Model Antitumor Assays", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "bcl-X Protein", 
            "type": "DefinedTerm"
          }
        ], 
        "author": [
          {
            "affiliation": {
              "alternateName": "Bilkent University", 
              "id": "https://www.grid.ac/institutes/grid.18376.3b", 
              "name": [
                "Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Saatci", 
            "givenName": "\u00d6zge", 
            "id": "sg:person.0732646263.37", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0732646263.37"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "German Cancer Research Center", 
              "id": "https://www.grid.ac/institutes/grid.7497.d", 
              "name": [
                "Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), INF580, 69120, Heidelberg, Germany"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Borgoni", 
            "givenName": "Simone", 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Bilkent University", 
              "id": "https://www.grid.ac/institutes/grid.18376.3b", 
              "name": [
                "Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Akbulut", 
            "givenName": "\u00d6zge", 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Bilkent University", 
              "id": "https://www.grid.ac/institutes/grid.18376.3b", 
              "name": [
                "Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Durmu\u015f", 
            "givenName": "Selvi", 
            "id": "sg:person.0770640067.46", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0770640067.46"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Bilkent University", 
              "id": "https://www.grid.ac/institutes/grid.18376.3b", 
              "name": [
                "Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Raza", 
            "givenName": "Umar", 
            "id": "sg:person.01274046110.33", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01274046110.33"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Bilkent University", 
              "id": "https://www.grid.ac/institutes/grid.18376.3b", 
              "name": [
                "Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Ey\u00fcpo\u011flu", 
            "givenName": "Erol", 
            "id": "sg:person.01000761463.95", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01000761463.95"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Bilkent University", 
              "id": "https://www.grid.ac/institutes/grid.18376.3b", 
              "name": [
                "Department of Computer Engineering, Bilkent University, 06800, Ankara, Turkey"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Alkan", 
            "givenName": "Can", 
            "id": "sg:person.0737070412.26", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0737070412.26"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Hacettepe University", 
              "id": "https://www.grid.ac/institutes/grid.14442.37", 
              "name": [
                "Department of Pathology, Hacettepe University School of Medicine, 06410, Ankara, Turkey"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Akyol", 
            "givenName": "Aytekin", 
            "id": "sg:person.01075747670.31", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01075747670.31"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Ba\u015fkent University", 
              "id": "https://www.grid.ac/institutes/grid.411548.d", 
              "name": [
                "Department of Medical Genetics, Ba\u015fkent University, 01250, Adana, Turkey"
              ], 
              "type": "Organization"
            }, 
            "familyName": "K\u00fct\u00fck", 
            "givenName": "\u00d6zg\u00fcr", 
            "id": "sg:person.01300762460.54", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01300762460.54"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "German Cancer Research Center", 
              "id": "https://www.grid.ac/institutes/grid.7497.d", 
              "name": [
                "Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), INF580, 69120, Heidelberg, Germany"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Wiemann", 
            "givenName": "Stefan", 
            "id": "sg:person.01045073444.63", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01045073444.63"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Bilkent University", 
              "id": "https://www.grid.ac/institutes/grid.18376.3b", 
              "name": [
                "Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey", 
                "National Nanotechnology Research Center (UNAM), Bilkent University, 06800, Ankara, Turkey"
              ], 
              "type": "Organization"
            }, 
            "familyName": "\u015eahin", 
            "givenName": "\u00d6zg\u00fcr", 
            "id": "sg:person.01345451532.89", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01345451532.89"
            ], 
            "type": "Person"
          }
        ], 
        "citation": [
          {
            "id": "sg:pub.10.1038/nrc1714", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1001299857", 
              "https://doi.org/10.1038/nrc1714"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrc1714", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1001299857", 
              "https://doi.org/10.1038/nrc1714"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1073/pnas.0606827104", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1001406660"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1158/0008-5472.can-08-1776", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1002574345"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/ncomms4887", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1003186097", 
              "https://doi.org/10.1038/ncomms4887"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1016/j.juro.2015.05.087", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1005449950"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/sj.onc.1208617", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1007133868", 
              "https://doi.org/10.1038/sj.onc.1208617"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/sj.onc.1208617", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1007133868", 
              "https://doi.org/10.1038/sj.onc.1208617"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1158/1535-7163.mct-06-0319", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1008007879"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/sj.onc.1208219", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1008998644", 
              "https://doi.org/10.1038/sj.onc.1208219"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/sj.onc.1208219", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1008998644", 
              "https://doi.org/10.1038/sj.onc.1208219"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1161/circulationaha.109.914820", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1009025627"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrc2212", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1010551352", 
              "https://doi.org/10.1038/nrc2212"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1007/s10549-011-1412-7", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1011772850", 
              "https://doi.org/10.1007/s10549-011-1412-7"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1158/1078-0432.ccr-11-0762", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1012575649"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1016/j.canlet.2010.02.002", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1013048258"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1016/j.cell.2015.11.062", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1013462087"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1128/mcb.26.6.2093-2108.2006", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1014898448"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.2147/cmar.s104447", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1015147724"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1056/nejmra043186", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1015198110"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1158/1535-7163.mct-06-0766", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1015864890"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1186/bcr2868", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1016830006", 
              "https://doi.org/10.1186/bcr2868"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1080/01926230701320337", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1017477247"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1080/01926230701320337", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1017477247"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1128/mcb.19.12.8469", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1017801518"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.18632/oncotarget.7043", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1017819496"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1158/0008-5472.can-12-2633", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1017983938"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1158/1535-7163.mct-10-0645", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1018819692"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1186/bcr3621", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1021348516", 
              "https://doi.org/10.1186/bcr3621"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1186/1747-1028-3-4", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1021457124", 
              "https://doi.org/10.1186/1747-1028-3-4"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nmeth1015", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1022621774", 
              "https://doi.org/10.1038/nmeth1015"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.3389/fonc.2012.00062", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1024202356"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrm2952", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1024676809", 
              "https://doi.org/10.1038/nrm2952"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1091/mbc.e11-09-0781", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1024810334"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1007/s10585-014-9688-8", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1026784798", 
              "https://doi.org/10.1007/s10585-014-9688-8"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1006/meth.2001.1262", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1027621591"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1006/meth.2001.1262", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1027621591"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/srep26766", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1027878324", 
              "https://doi.org/10.1038/srep26766"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1074/jbc.273.46.30777", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1029491178"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1586/era.10.226", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1030015126"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nprot.2012.016", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1030124536", 
              "https://doi.org/10.1038/nprot.2012.016"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/srep32541", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1031438232", 
              "https://doi.org/10.1038/srep32541"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/srep32541", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1031438232", 
              "https://doi.org/10.1038/srep32541"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1158/0008-5472.can-09-2181", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1031580979"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.3322/caac.21332", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1032745321"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1083/jcb.200309035", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1032970924"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1158/1535-7163.mct-08-1038", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1033809700"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrm2163", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1034186396", 
              "https://doi.org/10.1038/nrm2163"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrm2163", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1034186396", 
              "https://doi.org/10.1038/nrm2163"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1186/gb-2013-14-10-r110", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1034400822", 
              "https://doi.org/10.1186/gb-2013-14-10-r110"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrc1841", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1035809252", 
              "https://doi.org/10.1038/nrc1841"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrc1841", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1035809252", 
              "https://doi.org/10.1038/nrc1841"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/onc.2016.129", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1037432107", 
              "https://doi.org/10.1038/onc.2016.129"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1182/blood-2014-03-560557", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1038905759"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrc3261", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1039488853", 
              "https://doi.org/10.1038/nrc3261"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1097/cad.0000000000000007", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1040310521"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1097/cad.0000000000000007", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1040310521"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1200/jco.2009.22.1507", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1040562515"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrm1401", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1041206037", 
              "https://doi.org/10.1038/nrm1401"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrm1401", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1041206037", 
              "https://doi.org/10.1038/nrm1401"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrm1401", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1041206037", 
              "https://doi.org/10.1038/nrm1401"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1158/0008-5472.can-12-1339-t", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1041457669"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrm3819", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1042225971", 
              "https://doi.org/10.1038/nrm3819"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1056/nejmoa1209124", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1042743567"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1073/pnas.96.7.3775", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1043237595"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1016/j.ajpath.2011.06.031", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1043491897"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.3109/10428190109097729", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1043844766"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/sj.onc.1210355", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1043868630", 
              "https://doi.org/10.1038/sj.onc.1210355"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.18632/oncotarget.10489", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1045113535"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1158/1078-0432.ccr-09-1380", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1047834255"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1158/0008-5472.can-07-5836", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1049020079"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1016/j.molcel.2016.09.016", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1049112945"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1186/1752-0509-3-1", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1049490622", 
              "https://doi.org/10.1186/1752-0509-3-1"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1074/jbc.c400545200", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1049849890"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1016/j.tranon.2015.03.010", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1050023503"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1586/14789450.2014.971113", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1051271876"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1016/j.clml.2015.04.046", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1052513235"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/cdd.2011.197", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1053322918", 
              "https://doi.org/10.1038/cdd.2011.197"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/oncsis.2012.16", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1053536812", 
              "https://doi.org/10.1038/oncsis.2012.16"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1038/sj.neo.7900213", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1056649154"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1182/blood-2015-03-634402", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1064122696"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.2174/1381612820999141029162811", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1069170144"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://app.dimensions.ai/details/publication/pub.1076989480", 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://app.dimensions.ai/details/publication/pub.1082252186", 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://app.dimensions.ai/details/publication/pub.1082459947", 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.2741/4558", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1084649847"
            ], 
            "type": "CreativeWork"
          }
        ], 
        "datePublished": "2018-04", 
        "datePublishedReg": "2018-04-01", 
        "description": "Trastuzumab-refractory, HER2 (human epidermal growth factor receptor 2)-positive breast cancer is commonly treated with trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the microtubule-targeting agent, DM1. However, drug response reduces greatly over time due to acquisition of resistance whose molecular mechanisms are mostly unknown. Here, we uncovered a novel mechanism of resistance against T-DM1 by combining whole transcriptome sequencing (RNA-Seq), proteomics and a targeted small interfering RNA (siRNA) sensitization screen for molecular level analysis of acquired and de novo T-DM1-resistant models of HER2-overexpressing breast cancer. We identified Polo-like kinase 1 (PLK1), a mitotic kinase, as a resistance mediator whose genomic as well as pharmacological inhibition restored drug sensitivity. Both acquired and de novo resistant models exhibited synergistic growth inhibition upon combination of T-DM1 with a selective PLK1 inhibitor, volasertib, at a wide concentration range of the two drugs. Mechanistically, T-DM1 sensitization upon PLK1 inhibition with volasertib was initiated by a spindle assembly checkpoint (SAC)-dependent mitotic arrest, leading to caspase activation, followed by DNA damage through CDK1-dependent phosphorylation and inactivation of Bcl-2/xL. Furthermore, we showed that Ser70 phosphorylation of Bcl-2 directly regulates apoptosis by disrupting the binding to and sequestration of the pro-apoptotic protein Bim. Importantly, T-DM1 resistance signature or PLK1 expression correlated with cell cycle progression and DNA repair, and predicted a lower sensitivity to taxane/trastuzumab combination in HER2-positive breast cancer patients. Finally, volasertib in combination with T-DM1 greatly synergized in models of T-DM1 resistance in terms of growth inhibition both in three dimensional (3D) cell culture and in vivo. Altogether, our results provide promising pre-clinical evidence for potential testing of T-DM1/volasertib combination in T-DM1 refractory HER2-positive breast cancer patients for whom there is currently no treatment available.", 
        "genre": "research_article", 
        "id": "sg:pub.10.1038/s41388-017-0108-9", 
        "inLanguage": [
          "en"
        ], 
        "isAccessibleForFree": false, 
        "isPartOf": [
          {
            "id": "sg:journal.1097543", 
            "issn": [
              "0950-9232", 
              "1476-5594"
            ], 
            "name": "Oncogene", 
            "type": "Periodical"
          }, 
          {
            "issueNumber": "17", 
            "type": "PublicationIssue"
          }, 
          {
            "type": "PublicationVolume", 
            "volumeNumber": "37"
          }
        ], 
        "name": "Targeting PLK1 overcomes T-DM1 resistance via CDK1-dependent phosphorylation and inactivation of Bcl-2/xL in HER2-positive breast cancer", 
        "pagination": "2251-2269", 
        "productId": [
          {
            "name": "readcube_id", 
            "type": "PropertyValue", 
            "value": [
              "bfdeeb8032b0c5aa7f85ef79fbe722c3fe50c992881b66c3037b3a515f9e0d3d"
            ]
          }, 
          {
            "name": "pubmed_id", 
            "type": "PropertyValue", 
            "value": [
              "29391599"
            ]
          }, 
          {
            "name": "nlm_unique_id", 
            "type": "PropertyValue", 
            "value": [
              "8711562"
            ]
          }, 
          {
            "name": "doi", 
            "type": "PropertyValue", 
            "value": [
              "10.1038/s41388-017-0108-9"
            ]
          }, 
          {
            "name": "dimensions_id", 
            "type": "PropertyValue", 
            "value": [
              "pub.1100749534"
            ]
          }
        ], 
        "sameAs": [
          "https://doi.org/10.1038/s41388-017-0108-9", 
          "https://app.dimensions.ai/details/publication/pub.1100749534"
        ], 
        "sdDataset": "articles", 
        "sdDatePublished": "2019-04-11T11:37", 
        "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
        "sdPublisher": {
          "name": "Springer Nature - SN SciGraph project", 
          "type": "Organization"
        }, 
        "sdSource": "s3://com-uberresearch-data-dimensions-target-20181106-alternative/cleanup/v134/2549eaecd7973599484d7c17b260dba0a4ecb94b/merge/v9/a6c9fde33151104705d4d7ff012ea9563521a3ce/jats-lookup/v90/0000000358_0000000358/records_127427_00000010.jsonl", 
        "type": "ScholarlyArticle", 
        "url": "https://www.nature.com/articles/s41388-017-0108-9"
      }
    ]
     

    Download the RDF metadata as:  json-ld nt turtle xml License info

    HOW TO GET THIS DATA PROGRAMMATICALLY:

    JSON-LD is a popular format for linked data which is fully compatible with JSON.

    curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1038/s41388-017-0108-9'

    N-Triples is a line-based linked data format ideal for batch operations.

    curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1038/s41388-017-0108-9'

    Turtle is a human-readable linked data format.

    curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1038/s41388-017-0108-9'

    RDF/XML is a standard XML format for linked data.

    curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/s41388-017-0108-9'


     

    This table displays all metadata directly associated to this object as RDF triples.

    480 TRIPLES      21 PREDICATES      125 URIs      42 LITERALS      30 BLANK NODES

    Subject Predicate Object
    1 sg:pub.10.1038/s41388-017-0108-9 schema:about N06c098055abd4363975a8209b4cfcffd
    2 N146278f498f64ad19477816f23512380
    3 N26fcb2578a074a7ba6c192367e12ef7a
    4 N46f56b1f51a141ebbc65126d22067e53
    5 N577fa2c9862144cd87c8686185ade7ad
    6 N67118c8260bb426e9e02e5d1d149dcac
    7 N6bb8f7ae387d4a8ebaaa4932772555c3
    8 N7bb6c2aca1cf4ba78764e99bda62fa58
    9 N83b8131120fb4169a10d22bdaf4f1346
    10 N99c8b596b3e9426d92694d64647b1c37
    11 N9a15c88169684b81b7703f8963d995a5
    12 Na79a6d6aef4a4336acebed9420f00131
    13 Nb434cb611e3e4f698729260bf485a32a
    14 Nb7313ad937af4addb27c83030742f433
    15 Nb8784d477f1144b8b84bdf0501c4ef44
    16 Nb902e4b604804584b4de5f9bf06b473a
    17 Nbc9eeeb45f4b4f93b7196296d7f9c4df
    18 Nc1c74194fdf14e2a964611af9feeacae
    19 Nd578a4ba10d64277902f8e8060250db2
    20 Ndc62ac83e9b94797a321b6493910788a
    21 Nef716f5c6ff94172adeb2196402ce264
    22 anzsrc-for:11
    23 anzsrc-for:1112
    24 schema:author N1424440b651947abaeb155d7720ca87d
    25 schema:citation sg:pub.10.1007/s10549-011-1412-7
    26 sg:pub.10.1007/s10585-014-9688-8
    27 sg:pub.10.1038/cdd.2011.197
    28 sg:pub.10.1038/ncomms4887
    29 sg:pub.10.1038/nmeth1015
    30 sg:pub.10.1038/nprot.2012.016
    31 sg:pub.10.1038/nrc1714
    32 sg:pub.10.1038/nrc1841
    33 sg:pub.10.1038/nrc2212
    34 sg:pub.10.1038/nrc3261
    35 sg:pub.10.1038/nrm1401
    36 sg:pub.10.1038/nrm2163
    37 sg:pub.10.1038/nrm2952
    38 sg:pub.10.1038/nrm3819
    39 sg:pub.10.1038/onc.2016.129
    40 sg:pub.10.1038/oncsis.2012.16
    41 sg:pub.10.1038/sj.onc.1208219
    42 sg:pub.10.1038/sj.onc.1208617
    43 sg:pub.10.1038/sj.onc.1210355
    44 sg:pub.10.1038/srep26766
    45 sg:pub.10.1038/srep32541
    46 sg:pub.10.1186/1747-1028-3-4
    47 sg:pub.10.1186/1752-0509-3-1
    48 sg:pub.10.1186/bcr2868
    49 sg:pub.10.1186/bcr3621
    50 sg:pub.10.1186/gb-2013-14-10-r110
    51 https://app.dimensions.ai/details/publication/pub.1076989480
    52 https://app.dimensions.ai/details/publication/pub.1082252186
    53 https://app.dimensions.ai/details/publication/pub.1082459947
    54 https://doi.org/10.1006/meth.2001.1262
    55 https://doi.org/10.1016/j.ajpath.2011.06.031
    56 https://doi.org/10.1016/j.canlet.2010.02.002
    57 https://doi.org/10.1016/j.cell.2015.11.062
    58 https://doi.org/10.1016/j.clml.2015.04.046
    59 https://doi.org/10.1016/j.juro.2015.05.087
    60 https://doi.org/10.1016/j.molcel.2016.09.016
    61 https://doi.org/10.1016/j.tranon.2015.03.010
    62 https://doi.org/10.1038/sj.neo.7900213
    63 https://doi.org/10.1056/nejmoa1209124
    64 https://doi.org/10.1056/nejmra043186
    65 https://doi.org/10.1073/pnas.0606827104
    66 https://doi.org/10.1073/pnas.96.7.3775
    67 https://doi.org/10.1074/jbc.273.46.30777
    68 https://doi.org/10.1074/jbc.c400545200
    69 https://doi.org/10.1080/01926230701320337
    70 https://doi.org/10.1083/jcb.200309035
    71 https://doi.org/10.1091/mbc.e11-09-0781
    72 https://doi.org/10.1097/cad.0000000000000007
    73 https://doi.org/10.1128/mcb.19.12.8469
    74 https://doi.org/10.1128/mcb.26.6.2093-2108.2006
    75 https://doi.org/10.1158/0008-5472.can-07-5836
    76 https://doi.org/10.1158/0008-5472.can-08-1776
    77 https://doi.org/10.1158/0008-5472.can-09-2181
    78 https://doi.org/10.1158/0008-5472.can-12-1339-t
    79 https://doi.org/10.1158/0008-5472.can-12-2633
    80 https://doi.org/10.1158/1078-0432.ccr-09-1380
    81 https://doi.org/10.1158/1078-0432.ccr-11-0762
    82 https://doi.org/10.1158/1535-7163.mct-06-0319
    83 https://doi.org/10.1158/1535-7163.mct-06-0766
    84 https://doi.org/10.1158/1535-7163.mct-08-1038
    85 https://doi.org/10.1158/1535-7163.mct-10-0645
    86 https://doi.org/10.1161/circulationaha.109.914820
    87 https://doi.org/10.1182/blood-2014-03-560557
    88 https://doi.org/10.1182/blood-2015-03-634402
    89 https://doi.org/10.1200/jco.2009.22.1507
    90 https://doi.org/10.1586/14789450.2014.971113
    91 https://doi.org/10.1586/era.10.226
    92 https://doi.org/10.18632/oncotarget.10489
    93 https://doi.org/10.18632/oncotarget.7043
    94 https://doi.org/10.2147/cmar.s104447
    95 https://doi.org/10.2174/1381612820999141029162811
    96 https://doi.org/10.2741/4558
    97 https://doi.org/10.3109/10428190109097729
    98 https://doi.org/10.3322/caac.21332
    99 https://doi.org/10.3389/fonc.2012.00062
    100 schema:datePublished 2018-04
    101 schema:datePublishedReg 2018-04-01
    102 schema:description Trastuzumab-refractory, HER2 (human epidermal growth factor receptor 2)-positive breast cancer is commonly treated with trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the microtubule-targeting agent, DM1. However, drug response reduces greatly over time due to acquisition of resistance whose molecular mechanisms are mostly unknown. Here, we uncovered a novel mechanism of resistance against T-DM1 by combining whole transcriptome sequencing (RNA-Seq), proteomics and a targeted small interfering RNA (siRNA) sensitization screen for molecular level analysis of acquired and de novo T-DM1-resistant models of HER2-overexpressing breast cancer. We identified Polo-like kinase 1 (PLK1), a mitotic kinase, as a resistance mediator whose genomic as well as pharmacological inhibition restored drug sensitivity. Both acquired and de novo resistant models exhibited synergistic growth inhibition upon combination of T-DM1 with a selective PLK1 inhibitor, volasertib, at a wide concentration range of the two drugs. Mechanistically, T-DM1 sensitization upon PLK1 inhibition with volasertib was initiated by a spindle assembly checkpoint (SAC)-dependent mitotic arrest, leading to caspase activation, followed by DNA damage through CDK1-dependent phosphorylation and inactivation of Bcl-2/xL. Furthermore, we showed that Ser70 phosphorylation of Bcl-2 directly regulates apoptosis by disrupting the binding to and sequestration of the pro-apoptotic protein Bim. Importantly, T-DM1 resistance signature or PLK1 expression correlated with cell cycle progression and DNA repair, and predicted a lower sensitivity to taxane/trastuzumab combination in HER2-positive breast cancer patients. Finally, volasertib in combination with T-DM1 greatly synergized in models of T-DM1 resistance in terms of growth inhibition both in three dimensional (3D) cell culture and in vivo. Altogether, our results provide promising pre-clinical evidence for potential testing of T-DM1/volasertib combination in T-DM1 refractory HER2-positive breast cancer patients for whom there is currently no treatment available.
    103 schema:genre research_article
    104 schema:inLanguage en
    105 schema:isAccessibleForFree false
    106 schema:isPartOf N6842b2326707418181ce980f40e2189e
    107 Nd91bfc30021347f98bd8dfa38ce9ead9
    108 sg:journal.1097543
    109 schema:name Targeting PLK1 overcomes T-DM1 resistance via CDK1-dependent phosphorylation and inactivation of Bcl-2/xL in HER2-positive breast cancer
    110 schema:pagination 2251-2269
    111 schema:productId N250b1d431502405babdfeaee4331e16b
    112 N2dd635ea87a94ebdbe86b698c8d6ad32
    113 Na402bb7e62bd4a398c36ff6dbe86a14a
    114 Nb145121bc537402ca617894145017df2
    115 Nfa75a1dddeff42d88c2d6ef56e90eece
    116 schema:sameAs https://app.dimensions.ai/details/publication/pub.1100749534
    117 https://doi.org/10.1038/s41388-017-0108-9
    118 schema:sdDatePublished 2019-04-11T11:37
    119 schema:sdLicense https://scigraph.springernature.com/explorer/license/
    120 schema:sdPublisher Ne928e92a5f8d457aaea98bfe16369681
    121 schema:url https://www.nature.com/articles/s41388-017-0108-9
    122 sgo:license sg:explorer/license/
    123 sgo:sdDataset articles
    124 rdf:type schema:ScholarlyArticle
    125 N06c098055abd4363975a8209b4cfcffd schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    126 schema:name Xenograft Model Antitumor Assays
    127 rdf:type schema:DefinedTerm
    128 N1424440b651947abaeb155d7720ca87d rdf:first sg:person.0732646263.37
    129 rdf:rest N6c4756eb6cc44ff9abc8ea7d474cf484
    130 N1438cc5ed4d34d65a2acd317f8f5bc02 rdf:first sg:person.01000761463.95
    131 rdf:rest N88d17a985edb41afa7b916205dd284fd
    132 N146278f498f64ad19477816f23512380 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    133 schema:name Trastuzumab
    134 rdf:type schema:DefinedTerm
    135 N250b1d431502405babdfeaee4331e16b schema:name doi
    136 schema:value 10.1038/s41388-017-0108-9
    137 rdf:type schema:PropertyValue
    138 N26fcb2578a074a7ba6c192367e12ef7a schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    139 schema:name Cell Cycle Proteins
    140 rdf:type schema:DefinedTerm
    141 N2dd635ea87a94ebdbe86b698c8d6ad32 schema:name dimensions_id
    142 schema:value pub.1100749534
    143 rdf:type schema:PropertyValue
    144 N46f56b1f51a141ebbc65126d22067e53 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    145 schema:name Proto-Oncogene Proteins c-bcl-2
    146 rdf:type schema:DefinedTerm
    147 N577fa2c9862144cd87c8686185ade7ad schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    148 schema:name Maytansine
    149 rdf:type schema:DefinedTerm
    150 N59790abaec364005b12a57cd77321792 rdf:first Na233e3d267c24a3389ad10a9647c691e
    151 rdf:rest Nde0ee4bb704d40098c54657b582e68b4
    152 N67118c8260bb426e9e02e5d1d149dcac schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    153 schema:name Phosphorylation
    154 rdf:type schema:DefinedTerm
    155 N6842b2326707418181ce980f40e2189e schema:issueNumber 17
    156 rdf:type schema:PublicationIssue
    157 N6bb8f7ae387d4a8ebaaa4932772555c3 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    158 schema:name Drug Synergism
    159 rdf:type schema:DefinedTerm
    160 N6c4756eb6cc44ff9abc8ea7d474cf484 rdf:first Nfd2b5d0fbed948b7a08dfbdd670547bd
    161 rdf:rest N59790abaec364005b12a57cd77321792
    162 N74658d9c3b8d4495a9ce5f9355aead6a rdf:first sg:person.01300762460.54
    163 rdf:rest Nc59cc17a31014839a6843f7f5624ad4f
    164 N7bb6c2aca1cf4ba78764e99bda62fa58 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    165 schema:name Pteridines
    166 rdf:type schema:DefinedTerm
    167 N83b8131120fb4169a10d22bdaf4f1346 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    168 schema:name Signal Transduction
    169 rdf:type schema:DefinedTerm
    170 N88d17a985edb41afa7b916205dd284fd rdf:first sg:person.0737070412.26
    171 rdf:rest Nccd5e1cae0fd4954baf1d8ceec930482
    172 N99c8b596b3e9426d92694d64647b1c37 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    173 schema:name Animals
    174 rdf:type schema:DefinedTerm
    175 N9a15c88169684b81b7703f8963d995a5 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    176 schema:name bcl-X Protein
    177 rdf:type schema:DefinedTerm
    178 Na233e3d267c24a3389ad10a9647c691e schema:affiliation https://www.grid.ac/institutes/grid.18376.3b
    179 schema:familyName Akbulut
    180 schema:givenName Özge
    181 rdf:type schema:Person
    182 Na402bb7e62bd4a398c36ff6dbe86a14a schema:name nlm_unique_id
    183 schema:value 8711562
    184 rdf:type schema:PropertyValue
    185 Na79a6d6aef4a4336acebed9420f00131 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    186 schema:name Humans
    187 rdf:type schema:DefinedTerm
    188 Nb145121bc537402ca617894145017df2 schema:name readcube_id
    189 schema:value bfdeeb8032b0c5aa7f85ef79fbe722c3fe50c992881b66c3037b3a515f9e0d3d
    190 rdf:type schema:PropertyValue
    191 Nb434cb611e3e4f698729260bf485a32a schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    192 schema:name Female
    193 rdf:type schema:DefinedTerm
    194 Nb7313ad937af4addb27c83030742f433 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    195 schema:name Breast Neoplasms
    196 rdf:type schema:DefinedTerm
    197 Nb8784d477f1144b8b84bdf0501c4ef44 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    198 schema:name Cell Line, Tumor
    199 rdf:type schema:DefinedTerm
    200 Nb902e4b604804584b4de5f9bf06b473a schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    201 schema:name Mice
    202 rdf:type schema:DefinedTerm
    203 Nbc9eeeb45f4b4f93b7196296d7f9c4df schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    204 schema:name Proto-Oncogene Proteins
    205 rdf:type schema:DefinedTerm
    206 Nc1c74194fdf14e2a964611af9feeacae schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    207 schema:name Protein-Serine-Threonine Kinases
    208 rdf:type schema:DefinedTerm
    209 Nc49b6e19ec694454a8d66900de9db3b9 rdf:first sg:person.01345451532.89
    210 rdf:rest rdf:nil
    211 Nc59cc17a31014839a6843f7f5624ad4f rdf:first sg:person.01045073444.63
    212 rdf:rest Nc49b6e19ec694454a8d66900de9db3b9
    213 Nccd5e1cae0fd4954baf1d8ceec930482 rdf:first sg:person.01075747670.31
    214 rdf:rest N74658d9c3b8d4495a9ce5f9355aead6a
    215 Nce1c54c42869487b9b6a5b431b5704c7 rdf:first sg:person.01274046110.33
    216 rdf:rest N1438cc5ed4d34d65a2acd317f8f5bc02
    217 Nd578a4ba10d64277902f8e8060250db2 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    218 schema:name Receptor, ErbB-2
    219 rdf:type schema:DefinedTerm
    220 Nd91bfc30021347f98bd8dfa38ce9ead9 schema:volumeNumber 37
    221 rdf:type schema:PublicationVolume
    222 Ndc62ac83e9b94797a321b6493910788a schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    223 schema:name Drug Resistance, Neoplasm
    224 rdf:type schema:DefinedTerm
    225 Nde0ee4bb704d40098c54657b582e68b4 rdf:first sg:person.0770640067.46
    226 rdf:rest Nce1c54c42869487b9b6a5b431b5704c7
    227 Ne928e92a5f8d457aaea98bfe16369681 schema:name Springer Nature - SN SciGraph project
    228 rdf:type schema:Organization
    229 Nef716f5c6ff94172adeb2196402ce264 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    230 schema:name CDC2 Protein Kinase
    231 rdf:type schema:DefinedTerm
    232 Nfa75a1dddeff42d88c2d6ef56e90eece schema:name pubmed_id
    233 schema:value 29391599
    234 rdf:type schema:PropertyValue
    235 Nfd2b5d0fbed948b7a08dfbdd670547bd schema:affiliation https://www.grid.ac/institutes/grid.7497.d
    236 schema:familyName Borgoni
    237 schema:givenName Simone
    238 rdf:type schema:Person
    239 anzsrc-for:11 schema:inDefinedTermSet anzsrc-for:
    240 schema:name Medical and Health Sciences
    241 rdf:type schema:DefinedTerm
    242 anzsrc-for:1112 schema:inDefinedTermSet anzsrc-for:
    243 schema:name Oncology and Carcinogenesis
    244 rdf:type schema:DefinedTerm
    245 sg:journal.1097543 schema:issn 0950-9232
    246 1476-5594
    247 schema:name Oncogene
    248 rdf:type schema:Periodical
    249 sg:person.01000761463.95 schema:affiliation https://www.grid.ac/institutes/grid.18376.3b
    250 schema:familyName Eyüpoğlu
    251 schema:givenName Erol
    252 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01000761463.95
    253 rdf:type schema:Person
    254 sg:person.01045073444.63 schema:affiliation https://www.grid.ac/institutes/grid.7497.d
    255 schema:familyName Wiemann
    256 schema:givenName Stefan
    257 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01045073444.63
    258 rdf:type schema:Person
    259 sg:person.01075747670.31 schema:affiliation https://www.grid.ac/institutes/grid.14442.37
    260 schema:familyName Akyol
    261 schema:givenName Aytekin
    262 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01075747670.31
    263 rdf:type schema:Person
    264 sg:person.01274046110.33 schema:affiliation https://www.grid.ac/institutes/grid.18376.3b
    265 schema:familyName Raza
    266 schema:givenName Umar
    267 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01274046110.33
    268 rdf:type schema:Person
    269 sg:person.01300762460.54 schema:affiliation https://www.grid.ac/institutes/grid.411548.d
    270 schema:familyName Kütük
    271 schema:givenName Özgür
    272 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01300762460.54
    273 rdf:type schema:Person
    274 sg:person.01345451532.89 schema:affiliation https://www.grid.ac/institutes/grid.18376.3b
    275 schema:familyName Şahin
    276 schema:givenName Özgür
    277 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01345451532.89
    278 rdf:type schema:Person
    279 sg:person.0732646263.37 schema:affiliation https://www.grid.ac/institutes/grid.18376.3b
    280 schema:familyName Saatci
    281 schema:givenName Özge
    282 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0732646263.37
    283 rdf:type schema:Person
    284 sg:person.0737070412.26 schema:affiliation https://www.grid.ac/institutes/grid.18376.3b
    285 schema:familyName Alkan
    286 schema:givenName Can
    287 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0737070412.26
    288 rdf:type schema:Person
    289 sg:person.0770640067.46 schema:affiliation https://www.grid.ac/institutes/grid.18376.3b
    290 schema:familyName Durmuş
    291 schema:givenName Selvi
    292 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0770640067.46
    293 rdf:type schema:Person
    294 sg:pub.10.1007/s10549-011-1412-7 schema:sameAs https://app.dimensions.ai/details/publication/pub.1011772850
    295 https://doi.org/10.1007/s10549-011-1412-7
    296 rdf:type schema:CreativeWork
    297 sg:pub.10.1007/s10585-014-9688-8 schema:sameAs https://app.dimensions.ai/details/publication/pub.1026784798
    298 https://doi.org/10.1007/s10585-014-9688-8
    299 rdf:type schema:CreativeWork
    300 sg:pub.10.1038/cdd.2011.197 schema:sameAs https://app.dimensions.ai/details/publication/pub.1053322918
    301 https://doi.org/10.1038/cdd.2011.197
    302 rdf:type schema:CreativeWork
    303 sg:pub.10.1038/ncomms4887 schema:sameAs https://app.dimensions.ai/details/publication/pub.1003186097
    304 https://doi.org/10.1038/ncomms4887
    305 rdf:type schema:CreativeWork
    306 sg:pub.10.1038/nmeth1015 schema:sameAs https://app.dimensions.ai/details/publication/pub.1022621774
    307 https://doi.org/10.1038/nmeth1015
    308 rdf:type schema:CreativeWork
    309 sg:pub.10.1038/nprot.2012.016 schema:sameAs https://app.dimensions.ai/details/publication/pub.1030124536
    310 https://doi.org/10.1038/nprot.2012.016
    311 rdf:type schema:CreativeWork
    312 sg:pub.10.1038/nrc1714 schema:sameAs https://app.dimensions.ai/details/publication/pub.1001299857
    313 https://doi.org/10.1038/nrc1714
    314 rdf:type schema:CreativeWork
    315 sg:pub.10.1038/nrc1841 schema:sameAs https://app.dimensions.ai/details/publication/pub.1035809252
    316 https://doi.org/10.1038/nrc1841
    317 rdf:type schema:CreativeWork
    318 sg:pub.10.1038/nrc2212 schema:sameAs https://app.dimensions.ai/details/publication/pub.1010551352
    319 https://doi.org/10.1038/nrc2212
    320 rdf:type schema:CreativeWork
    321 sg:pub.10.1038/nrc3261 schema:sameAs https://app.dimensions.ai/details/publication/pub.1039488853
    322 https://doi.org/10.1038/nrc3261
    323 rdf:type schema:CreativeWork
    324 sg:pub.10.1038/nrm1401 schema:sameAs https://app.dimensions.ai/details/publication/pub.1041206037
    325 https://doi.org/10.1038/nrm1401
    326 rdf:type schema:CreativeWork
    327 sg:pub.10.1038/nrm2163 schema:sameAs https://app.dimensions.ai/details/publication/pub.1034186396
    328 https://doi.org/10.1038/nrm2163
    329 rdf:type schema:CreativeWork
    330 sg:pub.10.1038/nrm2952 schema:sameAs https://app.dimensions.ai/details/publication/pub.1024676809
    331 https://doi.org/10.1038/nrm2952
    332 rdf:type schema:CreativeWork
    333 sg:pub.10.1038/nrm3819 schema:sameAs https://app.dimensions.ai/details/publication/pub.1042225971
    334 https://doi.org/10.1038/nrm3819
    335 rdf:type schema:CreativeWork
    336 sg:pub.10.1038/onc.2016.129 schema:sameAs https://app.dimensions.ai/details/publication/pub.1037432107
    337 https://doi.org/10.1038/onc.2016.129
    338 rdf:type schema:CreativeWork
    339 sg:pub.10.1038/oncsis.2012.16 schema:sameAs https://app.dimensions.ai/details/publication/pub.1053536812
    340 https://doi.org/10.1038/oncsis.2012.16
    341 rdf:type schema:CreativeWork
    342 sg:pub.10.1038/sj.onc.1208219 schema:sameAs https://app.dimensions.ai/details/publication/pub.1008998644
    343 https://doi.org/10.1038/sj.onc.1208219
    344 rdf:type schema:CreativeWork
    345 sg:pub.10.1038/sj.onc.1208617 schema:sameAs https://app.dimensions.ai/details/publication/pub.1007133868
    346 https://doi.org/10.1038/sj.onc.1208617
    347 rdf:type schema:CreativeWork
    348 sg:pub.10.1038/sj.onc.1210355 schema:sameAs https://app.dimensions.ai/details/publication/pub.1043868630
    349 https://doi.org/10.1038/sj.onc.1210355
    350 rdf:type schema:CreativeWork
    351 sg:pub.10.1038/srep26766 schema:sameAs https://app.dimensions.ai/details/publication/pub.1027878324
    352 https://doi.org/10.1038/srep26766
    353 rdf:type schema:CreativeWork
    354 sg:pub.10.1038/srep32541 schema:sameAs https://app.dimensions.ai/details/publication/pub.1031438232
    355 https://doi.org/10.1038/srep32541
    356 rdf:type schema:CreativeWork
    357 sg:pub.10.1186/1747-1028-3-4 schema:sameAs https://app.dimensions.ai/details/publication/pub.1021457124
    358 https://doi.org/10.1186/1747-1028-3-4
    359 rdf:type schema:CreativeWork
    360 sg:pub.10.1186/1752-0509-3-1 schema:sameAs https://app.dimensions.ai/details/publication/pub.1049490622
    361 https://doi.org/10.1186/1752-0509-3-1
    362 rdf:type schema:CreativeWork
    363 sg:pub.10.1186/bcr2868 schema:sameAs https://app.dimensions.ai/details/publication/pub.1016830006
    364 https://doi.org/10.1186/bcr2868
    365 rdf:type schema:CreativeWork
    366 sg:pub.10.1186/bcr3621 schema:sameAs https://app.dimensions.ai/details/publication/pub.1021348516
    367 https://doi.org/10.1186/bcr3621
    368 rdf:type schema:CreativeWork
    369 sg:pub.10.1186/gb-2013-14-10-r110 schema:sameAs https://app.dimensions.ai/details/publication/pub.1034400822
    370 https://doi.org/10.1186/gb-2013-14-10-r110
    371 rdf:type schema:CreativeWork
    372 https://app.dimensions.ai/details/publication/pub.1076989480 schema:CreativeWork
    373 https://app.dimensions.ai/details/publication/pub.1082252186 schema:CreativeWork
    374 https://app.dimensions.ai/details/publication/pub.1082459947 schema:CreativeWork
    375 https://doi.org/10.1006/meth.2001.1262 schema:sameAs https://app.dimensions.ai/details/publication/pub.1027621591
    376 rdf:type schema:CreativeWork
    377 https://doi.org/10.1016/j.ajpath.2011.06.031 schema:sameAs https://app.dimensions.ai/details/publication/pub.1043491897
    378 rdf:type schema:CreativeWork
    379 https://doi.org/10.1016/j.canlet.2010.02.002 schema:sameAs https://app.dimensions.ai/details/publication/pub.1013048258
    380 rdf:type schema:CreativeWork
    381 https://doi.org/10.1016/j.cell.2015.11.062 schema:sameAs https://app.dimensions.ai/details/publication/pub.1013462087
    382 rdf:type schema:CreativeWork
    383 https://doi.org/10.1016/j.clml.2015.04.046 schema:sameAs https://app.dimensions.ai/details/publication/pub.1052513235
    384 rdf:type schema:CreativeWork
    385 https://doi.org/10.1016/j.juro.2015.05.087 schema:sameAs https://app.dimensions.ai/details/publication/pub.1005449950
    386 rdf:type schema:CreativeWork
    387 https://doi.org/10.1016/j.molcel.2016.09.016 schema:sameAs https://app.dimensions.ai/details/publication/pub.1049112945
    388 rdf:type schema:CreativeWork
    389 https://doi.org/10.1016/j.tranon.2015.03.010 schema:sameAs https://app.dimensions.ai/details/publication/pub.1050023503
    390 rdf:type schema:CreativeWork
    391 https://doi.org/10.1038/sj.neo.7900213 schema:sameAs https://app.dimensions.ai/details/publication/pub.1056649154
    392 rdf:type schema:CreativeWork
    393 https://doi.org/10.1056/nejmoa1209124 schema:sameAs https://app.dimensions.ai/details/publication/pub.1042743567
    394 rdf:type schema:CreativeWork
    395 https://doi.org/10.1056/nejmra043186 schema:sameAs https://app.dimensions.ai/details/publication/pub.1015198110
    396 rdf:type schema:CreativeWork
    397 https://doi.org/10.1073/pnas.0606827104 schema:sameAs https://app.dimensions.ai/details/publication/pub.1001406660
    398 rdf:type schema:CreativeWork
    399 https://doi.org/10.1073/pnas.96.7.3775 schema:sameAs https://app.dimensions.ai/details/publication/pub.1043237595
    400 rdf:type schema:CreativeWork
    401 https://doi.org/10.1074/jbc.273.46.30777 schema:sameAs https://app.dimensions.ai/details/publication/pub.1029491178
    402 rdf:type schema:CreativeWork
    403 https://doi.org/10.1074/jbc.c400545200 schema:sameAs https://app.dimensions.ai/details/publication/pub.1049849890
    404 rdf:type schema:CreativeWork
    405 https://doi.org/10.1080/01926230701320337 schema:sameAs https://app.dimensions.ai/details/publication/pub.1017477247
    406 rdf:type schema:CreativeWork
    407 https://doi.org/10.1083/jcb.200309035 schema:sameAs https://app.dimensions.ai/details/publication/pub.1032970924
    408 rdf:type schema:CreativeWork
    409 https://doi.org/10.1091/mbc.e11-09-0781 schema:sameAs https://app.dimensions.ai/details/publication/pub.1024810334
    410 rdf:type schema:CreativeWork
    411 https://doi.org/10.1097/cad.0000000000000007 schema:sameAs https://app.dimensions.ai/details/publication/pub.1040310521
    412 rdf:type schema:CreativeWork
    413 https://doi.org/10.1128/mcb.19.12.8469 schema:sameAs https://app.dimensions.ai/details/publication/pub.1017801518
    414 rdf:type schema:CreativeWork
    415 https://doi.org/10.1128/mcb.26.6.2093-2108.2006 schema:sameAs https://app.dimensions.ai/details/publication/pub.1014898448
    416 rdf:type schema:CreativeWork
    417 https://doi.org/10.1158/0008-5472.can-07-5836 schema:sameAs https://app.dimensions.ai/details/publication/pub.1049020079
    418 rdf:type schema:CreativeWork
    419 https://doi.org/10.1158/0008-5472.can-08-1776 schema:sameAs https://app.dimensions.ai/details/publication/pub.1002574345
    420 rdf:type schema:CreativeWork
    421 https://doi.org/10.1158/0008-5472.can-09-2181 schema:sameAs https://app.dimensions.ai/details/publication/pub.1031580979
    422 rdf:type schema:CreativeWork
    423 https://doi.org/10.1158/0008-5472.can-12-1339-t schema:sameAs https://app.dimensions.ai/details/publication/pub.1041457669
    424 rdf:type schema:CreativeWork
    425 https://doi.org/10.1158/0008-5472.can-12-2633 schema:sameAs https://app.dimensions.ai/details/publication/pub.1017983938
    426 rdf:type schema:CreativeWork
    427 https://doi.org/10.1158/1078-0432.ccr-09-1380 schema:sameAs https://app.dimensions.ai/details/publication/pub.1047834255
    428 rdf:type schema:CreativeWork
    429 https://doi.org/10.1158/1078-0432.ccr-11-0762 schema:sameAs https://app.dimensions.ai/details/publication/pub.1012575649
    430 rdf:type schema:CreativeWork
    431 https://doi.org/10.1158/1535-7163.mct-06-0319 schema:sameAs https://app.dimensions.ai/details/publication/pub.1008007879
    432 rdf:type schema:CreativeWork
    433 https://doi.org/10.1158/1535-7163.mct-06-0766 schema:sameAs https://app.dimensions.ai/details/publication/pub.1015864890
    434 rdf:type schema:CreativeWork
    435 https://doi.org/10.1158/1535-7163.mct-08-1038 schema:sameAs https://app.dimensions.ai/details/publication/pub.1033809700
    436 rdf:type schema:CreativeWork
    437 https://doi.org/10.1158/1535-7163.mct-10-0645 schema:sameAs https://app.dimensions.ai/details/publication/pub.1018819692
    438 rdf:type schema:CreativeWork
    439 https://doi.org/10.1161/circulationaha.109.914820 schema:sameAs https://app.dimensions.ai/details/publication/pub.1009025627
    440 rdf:type schema:CreativeWork
    441 https://doi.org/10.1182/blood-2014-03-560557 schema:sameAs https://app.dimensions.ai/details/publication/pub.1038905759
    442 rdf:type schema:CreativeWork
    443 https://doi.org/10.1182/blood-2015-03-634402 schema:sameAs https://app.dimensions.ai/details/publication/pub.1064122696
    444 rdf:type schema:CreativeWork
    445 https://doi.org/10.1200/jco.2009.22.1507 schema:sameAs https://app.dimensions.ai/details/publication/pub.1040562515
    446 rdf:type schema:CreativeWork
    447 https://doi.org/10.1586/14789450.2014.971113 schema:sameAs https://app.dimensions.ai/details/publication/pub.1051271876
    448 rdf:type schema:CreativeWork
    449 https://doi.org/10.1586/era.10.226 schema:sameAs https://app.dimensions.ai/details/publication/pub.1030015126
    450 rdf:type schema:CreativeWork
    451 https://doi.org/10.18632/oncotarget.10489 schema:sameAs https://app.dimensions.ai/details/publication/pub.1045113535
    452 rdf:type schema:CreativeWork
    453 https://doi.org/10.18632/oncotarget.7043 schema:sameAs https://app.dimensions.ai/details/publication/pub.1017819496
    454 rdf:type schema:CreativeWork
    455 https://doi.org/10.2147/cmar.s104447 schema:sameAs https://app.dimensions.ai/details/publication/pub.1015147724
    456 rdf:type schema:CreativeWork
    457 https://doi.org/10.2174/1381612820999141029162811 schema:sameAs https://app.dimensions.ai/details/publication/pub.1069170144
    458 rdf:type schema:CreativeWork
    459 https://doi.org/10.2741/4558 schema:sameAs https://app.dimensions.ai/details/publication/pub.1084649847
    460 rdf:type schema:CreativeWork
    461 https://doi.org/10.3109/10428190109097729 schema:sameAs https://app.dimensions.ai/details/publication/pub.1043844766
    462 rdf:type schema:CreativeWork
    463 https://doi.org/10.3322/caac.21332 schema:sameAs https://app.dimensions.ai/details/publication/pub.1032745321
    464 rdf:type schema:CreativeWork
    465 https://doi.org/10.3389/fonc.2012.00062 schema:sameAs https://app.dimensions.ai/details/publication/pub.1024202356
    466 rdf:type schema:CreativeWork
    467 https://www.grid.ac/institutes/grid.14442.37 schema:alternateName Hacettepe University
    468 schema:name Department of Pathology, Hacettepe University School of Medicine, 06410, Ankara, Turkey
    469 rdf:type schema:Organization
    470 https://www.grid.ac/institutes/grid.18376.3b schema:alternateName Bilkent University
    471 schema:name Department of Computer Engineering, Bilkent University, 06800, Ankara, Turkey
    472 Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800, Ankara, Turkey
    473 National Nanotechnology Research Center (UNAM), Bilkent University, 06800, Ankara, Turkey
    474 rdf:type schema:Organization
    475 https://www.grid.ac/institutes/grid.411548.d schema:alternateName Başkent University
    476 schema:name Department of Medical Genetics, Başkent University, 01250, Adana, Turkey
    477 rdf:type schema:Organization
    478 https://www.grid.ac/institutes/grid.7497.d schema:alternateName German Cancer Research Center
    479 schema:name Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), INF580, 69120, Heidelberg, Germany
    480 rdf:type schema:Organization
     




    Preview window. Press ESC to close (or click here)


    ...