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

// Helen Creedon 1 , Laura Gomez-Cuadrado 1 , Žygimantė Tarnauskaitė 1 , Jozef Balla 1 , Marta Canel 1 , Kenneth G. MacLeod 1 , Bryan Serrels 1 , Craig Fraser 1 , Asier Unciti-Broceta 1 , Natasha Tracey 1 , Thierry Le Bihan 2 , Teresa Klinowska 3 , Andrew H. Sims 1 , Adam Byron 1 , Valerie G. Brunton 1 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 Correspondence to: Valerie G. Brunton, e-mail: v.brunton@ed.ac.uk Adam Byron, e-mail: adam.byron@igmm.ed.ac.uk Keywords: resistance, breast cancer, EMT, HER2, proteomics Received: December 09, 2015      Accepted: January 26, 2016      Published: February 11, 2016 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.