title: Activated d16HER2 homodimers and SRC kinase mediate optimal efficacy for trastuzumab.
abstract: A splice isoform of the HER2 receptor that lacks exon 16 (d16HER2) is expressed in many HER2-positive breast tumors, where it has been linked with resistance to the HER2-targeting antibody trastuzumab, but the impact of d16HER2 on tumor pathobiology and therapeutic response remains uncertain. Here, we provide genetic evidence in transgenic mice that expression of d16HER2 is sufficient to accelerate mammary tumorigenesis and improve the response to trastuzumab. A comparative analysis of effector signaling pathways activated by d16HER2 and wild-type HER2 revealed that d16HER2 was optimally functional through a link to SRC activation (pSRC). Clinically, HER2-positive breast cancers from patients who received trastuzumab exhibited a positive correlation in d16HER2 and pSRC abundance, consistent with the mouse genetic results. Moreover, patients expressing high pSRC or an activated "d16HER2 metagene" were found to derive the greatest benefit from trastuzumab treatment. Overall, our results establish the d16HER2 signaling axis as a signature for decreased risk of relapse after trastuzumab treatment.
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Castagnoli
authors.affiliation: Aging Research Centre, G. D'Annunzio University, Chieti, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Iezzi
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Gaia C
authors.initials: GC
authors.lastname: Ghedini
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Ciravolo
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Marzano
authors.affiliation: Aging Research Centre, G. D'Annunzio University, Chieti, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Lamolinara
authors.affiliation: C. Gandini Medical Oncology, Bone Marrow Transplantation Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Zappasodi
authors.affiliation: Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Gasparini
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Campiglio
authors.affiliation: Department of Bioscience and Biotechnology, University of Camerino, Camerino, Italy.
authors.forename: Augusto
authors.initials: A
authors.lastname: Amici
authors.affiliation: Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Chiodoni
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Palladini
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Lollini
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Triulzi
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Menard
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Nanni
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Elda
authors.initials: E
authors.lastname: Tagliabue
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy. serenella.pupa@istitutotumori.mi.it.
authors.forename: Serenella M
authors.initials: SM
authors.lastname: Pupa
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics*; D055503:Protein Multimerization / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D000068878:Trastuzumab; D019061:src-Family Kinases / Q000235:genetics*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D020033:Protein Isoforms; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D019061:src-Family Kinases; C508053:ERBB2 protein, human