2026-04-23T00:03:35Zhttps://riubu.ubu.es/oai/request

oai:riubu.ubu.es:10259/97922024-12-18T01:05:24Zcom_10259_6168com_10259_5086com_10259_2604col_10259_6169

Identification of novel pathways linking epithelial-to-mesenchymal transition with resistance to HER2-targeted therapy Creedon, Helen Gómez Cuadrado, Laura Tarnauskaitė, Žygimantė Balla, Jozef Canel, Marta MacLeod, Kenneth G. Serrels, Bryan Fraser, Craig Unciti-Broceta, Asier Tracey, Natasha Le Bihan, Thierry Kilnowska, Teresa Sims, Andrew H. Byron, Adam Brunton, Valerie G. Resistance Breast cancer EMT HER2 Proteomics Salud Medicina Oncología Health Medicine Oncology 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. This work was supported by Cancer Research UK grants (C157/A15703 and C6088/A12063). The mass spectrometer was funded by a Wellcome Trust Institutional Strategic Support Fund award and a Wellcome Trust Strategic Award to the University of Edinburgh Centre for Immunity, Infection and Evolution. SynthSys is a Centre for Integrative Systems Biology funded by the Biotechnology and Biological Sciences Research Council and Engineering and Physical Sciences Research Council (reference BB/D019621/1). 2024-12-17T09:28:07Z 2024-12-17T09:28:07Z 2016-02 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://hdl.handle.net/10259/9792 10.18632/oncotarget.7317 1949-2553 eng Oncotarget. 2016, V. 7, n. 10, p. 11539-11552 https://doi.org/10.18632/oncotarget.7317 Atribución 4.0 Internacional http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf Impact Journals