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MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701
Targeting the MEK/ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI3K/AKT activation and thus contributes to the desensitization of cancer cells to MEK inhibitors. The underlying molecular mechanism of this event is not yet u...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579385/ https://www.ncbi.nlm.nih.gov/pubmed/28632938 http://dx.doi.org/10.1002/1878-0261.12102 |
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author | Chen, Chia‐Hung Hsia, Te‐Chun Yeh, Ming‐Hsin Chen, Tsung‐Wei Chen, Yun‐Ju Chen, Jung‐Tsu Wei, Ya‐Ling Tu, Chih‐Yen Huang, Wei‐Chien |
author_facet | Chen, Chia‐Hung Hsia, Te‐Chun Yeh, Ming‐Hsin Chen, Tsung‐Wei Chen, Yun‐Ju Chen, Jung‐Tsu Wei, Ya‐Ling Tu, Chih‐Yen Huang, Wei‐Chien |
author_sort | Chen, Chia‐Hung |
collection | PubMed |
description | Targeting the MEK/ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI3K/AKT activation and thus contributes to the desensitization of cancer cells to MEK inhibitors. The underlying molecular mechanism of this event is not yet understood. In this study, our data showed that the induction of Akt activity by MEK inhibitors was specifically observed in HER2‐positive breast cancer cells. Silence of HER2, or overexpression of HER2 kinase‐dead mutant, prevents the induction of Akt activation in response to MEK inhibition, indicating HER2 as a critical regulator for this event. Furthermore, HER2 Thr701 was demonstrated as a direct phosphorylation target of ERK1/2. Inhibition of this specific phosphorylation prolonged the dimerization of HER2 with EGFR in a clathrin‐dependent manner, leading to the enhanced activation of HER2 and EGFR tyrosine kinase and their downstream Akt pathway. These results suggest that suppression of ERK‐mediated HER2 Thr701 phosphorylation contributes to MEK inhibitor‐induced Akt activation. |
format | Online Article Text |
id | pubmed-5579385 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-55793852017-09-06 MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701 Chen, Chia‐Hung Hsia, Te‐Chun Yeh, Ming‐Hsin Chen, Tsung‐Wei Chen, Yun‐Ju Chen, Jung‐Tsu Wei, Ya‐Ling Tu, Chih‐Yen Huang, Wei‐Chien Mol Oncol Research Articles Targeting the MEK/ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI3K/AKT activation and thus contributes to the desensitization of cancer cells to MEK inhibitors. The underlying molecular mechanism of this event is not yet understood. In this study, our data showed that the induction of Akt activity by MEK inhibitors was specifically observed in HER2‐positive breast cancer cells. Silence of HER2, or overexpression of HER2 kinase‐dead mutant, prevents the induction of Akt activation in response to MEK inhibition, indicating HER2 as a critical regulator for this event. Furthermore, HER2 Thr701 was demonstrated as a direct phosphorylation target of ERK1/2. Inhibition of this specific phosphorylation prolonged the dimerization of HER2 with EGFR in a clathrin‐dependent manner, leading to the enhanced activation of HER2 and EGFR tyrosine kinase and their downstream Akt pathway. These results suggest that suppression of ERK‐mediated HER2 Thr701 phosphorylation contributes to MEK inhibitor‐induced Akt activation. John Wiley and Sons Inc. 2017-07-19 2017-09 /pmc/articles/PMC5579385/ /pubmed/28632938 http://dx.doi.org/10.1002/1878-0261.12102 Text en © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Chen, Chia‐Hung Hsia, Te‐Chun Yeh, Ming‐Hsin Chen, Tsung‐Wei Chen, Yun‐Ju Chen, Jung‐Tsu Wei, Ya‐Ling Tu, Chih‐Yen Huang, Wei‐Chien MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701 |
title |
MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701 |
title_full |
MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701 |
title_fullStr |
MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701 |
title_full_unstemmed |
MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701 |
title_short |
MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701 |
title_sort | mek inhibitors induce akt activation and drug resistance by suppressing negative feedback erk‐mediated her2 phosphorylation at thr701 |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579385/ https://www.ncbi.nlm.nih.gov/pubmed/28632938 http://dx.doi.org/10.1002/1878-0261.12102 |
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