title: Identification of novel pathways linking epithelial-to-mesenchymal transition with resistance to HER2-targeted therapy.
abstract: Resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapies in the treatment of HER2-positive breast cancer is a major clinical problem. To identify pathways linked to resistance, we generated HER2-positive breast cancer cell lines which are resistant to either lapatinib or AZD8931, two pan-HER family kinase inhibitors. Resistance was HER2 independent and was associated with epithelial-to-mesenchymal transition (EMT), resulting in increased proliferation and migration of the resistant cells. Using a global proteomics approach, we identified a novel set of EMT-associated proteins linked to HER2-independent resistance. We demonstrate that a subset of these EMT-associated genes is predictive of prognosis within the ERBB2 subtype of human breast cancers. Furthermore, targeting the EMT-associated kinases Src and Axl potently inhibited proliferation of the resistant cells, and inhibitors to these kinases may provide additional options for the treatment of HER2-independent resistance in tumors.
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Creedon
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Gómez-Cuadrado
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Žygimantė
authors.initials: Ž
authors.lastname: Tarnauskaitė
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Jozef
authors.initials: J
authors.lastname: Balla
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Canel
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: MacLeod
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Bryan
authors.initials: B
authors.lastname: Serrels
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Craig
authors.initials: C
authors.lastname: Fraser
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Asier
authors.initials: A
authors.lastname: Unciti-Broceta
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Natasha
authors.initials: N
authors.lastname: Tracey
authors.affiliation: SynthSys, University of Edinburgh, Edinburgh EH9 3BF, UK.
authors.forename: Thierry
authors.initials: T
authors.lastname: Le Bihan
authors.affiliation: AstraZeneca Oncology iMed, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: Teresa
authors.initials: T
authors.lastname: Klinowska
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Sims
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Byron
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Valerie G
authors.initials: VG
authors.lastname: Brunton
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D000077341:Lapatinib; D058990:Molecular Targeted Therapy; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D040901:Proteomics; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C548875:AZD 8931; C508053:ERBB2 protein, human
keywords: EMT; HER2; breast cancer; proteomics; resistance