1. Identification of novel pathways linking epithelial-to-mesenchymal transition with resistance to HER2-targeted therapy.
- Author
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Creedon H, Gómez-Cuadrado L, Tarnauskaitė Ž, Balla J, Canel M, MacLeod KG, Serrels B, Fraser C, Unciti-Broceta A, Tracey N, Le Bihan T, Klinowska T, Sims AH, Byron A, and Brunton VG
- Subjects
- Breast Neoplasms enzymology, Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Line, Tumor, Drug Resistance, Neoplasm, Epithelial-Mesenchymal Transition, Female, Humans, Lapatinib, Molecular Targeted Therapy, Prognosis, Proteomics, Quinazolines pharmacology, Receptor, ErbB-2 antagonists & inhibitors, Signal Transduction, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Protein Kinase Inhibitors pharmacology, Receptor, ErbB-2 metabolism
- 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.
- Published
- 2016
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