Cargando…

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 AZD8...

Descripción completa

Detalles Bibliográficos
Autores principales: 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, Klinowska, Teresa, Sims, Andrew H., Byron, Adam, Brunton, Valerie G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905492/
https://www.ncbi.nlm.nih.gov/pubmed/26883193
http://dx.doi.org/10.18632/oncotarget.7317
_version_ 1782437272387321856
author 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
Klinowska, Teresa
Sims, Andrew H.
Byron, Adam
Brunton, Valerie G.
author_facet 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
Klinowska, Teresa
Sims, Andrew H.
Byron, Adam
Brunton, Valerie G.
author_sort Creedon, Helen
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4905492
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-49054922016-06-24 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 Klinowska, Teresa Sims, Andrew H. Byron, Adam Brunton, Valerie G. Oncotarget Research Paper 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. Impact Journals LLC 2016-02-11 /pmc/articles/PMC4905492/ /pubmed/26883193 http://dx.doi.org/10.18632/oncotarget.7317 Text en Copyright: © 2016 Creedon et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
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
Klinowska, Teresa
Sims, Andrew H.
Byron, Adam
Brunton, Valerie G.
Identification of novel pathways linking epithelial-to-mesenchymal transition with resistance to HER2-targeted therapy
title Identification of novel pathways linking epithelial-to-mesenchymal transition with resistance to HER2-targeted therapy
title_full Identification of novel pathways linking epithelial-to-mesenchymal transition with resistance to HER2-targeted therapy
title_fullStr Identification of novel pathways linking epithelial-to-mesenchymal transition with resistance to HER2-targeted therapy
title_full_unstemmed Identification of novel pathways linking epithelial-to-mesenchymal transition with resistance to HER2-targeted therapy
title_short Identification of novel pathways linking epithelial-to-mesenchymal transition with resistance to HER2-targeted therapy
title_sort identification of novel pathways linking epithelial-to-mesenchymal transition with resistance to her2-targeted therapy
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905492/
https://www.ncbi.nlm.nih.gov/pubmed/26883193
http://dx.doi.org/10.18632/oncotarget.7317
work_keys_str_mv AT creedonhelen identificationofnovelpathwayslinkingepithelialtomesenchymaltransitionwithresistancetoher2targetedtherapy
AT gomezcuadradolaura identificationofnovelpathwayslinkingepithelialtomesenchymaltransitionwithresistancetoher2targetedtherapy
AT tarnauskaitezygimante identificationofnovelpathwayslinkingepithelialtomesenchymaltransitionwithresistancetoher2targetedtherapy
AT ballajozef identificationofnovelpathwayslinkingepithelialtomesenchymaltransitionwithresistancetoher2targetedtherapy
AT canelmarta identificationofnovelpathwayslinkingepithelialtomesenchymaltransitionwithresistancetoher2targetedtherapy
AT macleodkennethg identificationofnovelpathwayslinkingepithelialtomesenchymaltransitionwithresistancetoher2targetedtherapy
AT serrelsbryan identificationofnovelpathwayslinkingepithelialtomesenchymaltransitionwithresistancetoher2targetedtherapy
AT frasercraig identificationofnovelpathwayslinkingepithelialtomesenchymaltransitionwithresistancetoher2targetedtherapy
AT uncitibrocetaasier identificationofnovelpathwayslinkingepithelialtomesenchymaltransitionwithresistancetoher2targetedtherapy
AT traceynatasha identificationofnovelpathwayslinkingepithelialtomesenchymaltransitionwithresistancetoher2targetedtherapy
AT lebihanthierry identificationofnovelpathwayslinkingepithelialtomesenchymaltransitionwithresistancetoher2targetedtherapy
AT klinowskateresa identificationofnovelpathwayslinkingepithelialtomesenchymaltransitionwithresistancetoher2targetedtherapy
AT simsandrewh identificationofnovelpathwayslinkingepithelialtomesenchymaltransitionwithresistancetoher2targetedtherapy
AT byronadam identificationofnovelpathwayslinkingepithelialtomesenchymaltransitionwithresistancetoher2targetedtherapy
AT bruntonvalerieg identificationofnovelpathwayslinkingepithelialtomesenchymaltransitionwithresistancetoher2targetedtherapy