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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
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.
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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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