Identification of novel pathways linking epithelial-to-mesenchymal transition with resistance to HER2-targeted therapy

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.


Helen Creedon,1 Laura Gomez-Cuadrado,1 Zygimanté Tarnauskaité,1 Jozef Balla,1 Marta Canel,1 Kenneth G. MacLeod,1 Bryan Serrels,1 Craig Graser,1 Asier Unciti-Broceta,1 Natasha Tracey,1 Thierry Le Bihan,2 Teresa Klinowska,3 Andrew H. Sims,1 Adam Byron,1 and Valerie G. Brunton1

  • 1. Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK
  • 2. SynthSys, University of Edinburgh, Edinburgh EH9 3BF, UK
  • 3. AstraZeneca Oncology iMed, Alderley Park, Macclesfield SK10 4TG, UK


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