Identification of novel pathways linking epithelial-to-mesenchymal transition with resistance to HER2-targeted therapy
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Helen Creedon1, Laura Gómez-Cuadrado1, Žygimantė Tarnauskaitė1, Jozef Balla1, Marta Canel1, Kenneth G. MacLeod1, Bryan Serrels1, Craig Fraser1, Asier Unciti-Broceta1, Natasha Tracey1, Thierry Le Bihan2, Teresa Klinowska3, Andrew H. Sims1, Adam Byron1, Valerie G. Brunton1
1Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK
2SynthSys, University of Edinburgh, Edinburgh EH9 3BF, UK
3AstraZeneca Oncology iMed, Alderley Park, Macclesfield SK10 4TG, UK
Valerie G. Brunton, e-mail: [email protected]
Adam Byron, e-mail: [email protected]
Keywords: resistance, breast cancer, EMT, HER2, proteomics
Received: December 09, 2015 Accepted: January 26, 2016 Published: February 11, 2016
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.
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