title: Targeting of preexisting and induced breast cancer stem cells with trastuzumab and trastuzumab emtansine (T-DM1).
abstract: The antibody trastuzumab (Herceptin) has substantially improved overall survival for patients with aggressive HER2-positive breast cancer. However, about 70% of all treated patients will experience relapse or disease progression. This may be related to an insufficient targeting of the CD44(high)CD24(low) breast cancer stem cell subset, which is not only highly resistant to chemotherapy and radiotherapy but also a poor target for trastuzumab due to low HER2 surface expression. Hence, we explored whether the new antibody-drug conjugate T-DM1, which consists of the potent chemotherapeutic DM1 coupled to trastuzumab, could improve the targeting of these tumor-initiating or metastasis-initiating cells. To this aim, primary HER2-overexpressing tumor cells as well as HER2-positive and HER2-negative breast cancer cell lines were treated with T-DM1, and effects on survival, colony formation, gene and protein expression as well as antibody internalization were assessed. This revealed that CD44(high)CD24(low)HER2(low) stem cell-like breast cancer cells show high endocytic activity and are thus particularly sensitive towards the antibody-drug conjugate T-DM1. Consequently, preexisting CD44(high)CD24(low) cancer stem cells were depleted by concentrations of T-DM1 that did not affect the bulk of the tumor cells. Likewise, colony formation was efficiently suppressed. Moreover, when tumor cells were cocultured with natural killer cells, antibody-dependent cell-mediated cytotoxicity was enhanced, and EMT-mediated induction of stem cell-like properties was prevented in differentiated tumor cells. Thus our study reveals an unanticipated targeting of stem cell-like breast cancer cells by T-DM1 that may contribute to the clinical efficacy of this recently approved antibody-drug conjugate.
authors.affiliation: Department for Obstetrics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Street 4, Würzburg 97080, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Diessner
authors.affiliation: Department for Obstetrics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Street 4, Würzburg 97080, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Bruttel
authors.affiliation: 1] Department for Obstetrics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Street 4, Würzburg 97080, Germany [2] Else-Kröner Research Training Program for Clinician Scientists, University of Würzburg Medical School, Josef-Schneider-Street 4, Würzburg 97080, Germany.
authors.forename: R G
authors.initials: RG
authors.lastname: Stein
authors.affiliation: Department for Obstetrics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Street 4, Würzburg 97080, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Horn
authors.affiliation: 1] Department for Obstetrics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Street 4, Würzburg 97080, Germany [2] Interdisciplinary Center for Clinical Research (IZKF), University of Würzburg Medical School, Josef-Schneider-Street 4, Würzburg 97080, Germany.
authors.forename: S F M
authors.initials: SF
authors.lastname: Häusler
authors.affiliation: Department for Obstetrics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Street 4, Würzburg 97080, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Dietl
authors.affiliation: 1] Department for Obstetrics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Street 4, Würzburg 97080, Germany [2] Interdisciplinary Center for Clinical Research (IZKF), University of Würzburg Medical School, Josef-Schneider-Street 4, Würzburg 97080, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hönig
authors.affiliation: 1] Department for Obstetrics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Street 4, Würzburg 97080, Germany [2] Interdisciplinary Center for Clinical Research (IZKF), University of Würzburg Medical School, Josef-Schneider-Street 4, Würzburg 97080, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Wischhusen
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D015703:Antigens, CD / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002999:Clone Cells; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects; D008453:Maytansine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D010641:Phenotype; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013997:Time Factors; D000068878:Trastuzumab; D055815:Young Adult
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab