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...
Main Authors: | , , , , , , , , |
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Format: | Article |
Language: | English |
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Wiley
2017-09-01
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Series: | Molecular Oncology |
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Online Access: | https://doi.org/10.1002/1878-0261.12102 |
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author | Chia‐Hung Chen Te‐Chun Hsia Ming‐Hsin Yeh Tsung‐Wei Chen Yun‐Ju Chen Jung‐Tsu Chen Ya‐Ling Wei Chih‐Yen Tu Wei‐Chien Huang |
author_facet | Chia‐Hung Chen Te‐Chun Hsia Ming‐Hsin Yeh Tsung‐Wei Chen Yun‐Ju Chen Jung‐Tsu Chen Ya‐Ling Wei Chih‐Yen Tu Wei‐Chien Huang |
author_sort | Chia‐Hung Chen |
collection | DOAJ |
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. |
first_indexed | 2024-04-11T13:32:44Z |
format | Article |
id | doaj.art-f270dd72f6c64bd298443c9247421096 |
institution | Directory Open Access Journal |
issn | 1574-7891 1878-0261 |
language | English |
last_indexed | 2024-04-11T13:32:44Z |
publishDate | 2017-09-01 |
publisher | Wiley |
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series | Molecular Oncology |
spelling | doaj.art-f270dd72f6c64bd298443c92474210962022-12-22T04:21:47ZengWileyMolecular Oncology1574-78911878-02612017-09-011191273128710.1002/1878-0261.12102MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701Chia‐Hung Chen0Te‐Chun Hsia1Ming‐Hsin Yeh2Tsung‐Wei Chen3Yun‐Ju Chen4Jung‐Tsu Chen5Ya‐Ling Wei6Chih‐Yen Tu7Wei‐Chien Huang8Graduate Institute of Clinical Medical Science China Medical University Taichung TaiwanDivision of Pulmonary and Critical Care Medicine Department of Internal Medicine China Medical University Hospital Taichung TaiwanDepartment of Surgery Chang Shan Medical University Taichung TaiwanDepartment of Pathology China Medical University Hospital Taichung TaiwanDepartment of Medical Research E‐Da Hospital Kaohsiung TaiwanGraduate Institute of Clinical Dentistry National Taiwan University Taipei TaiwanCenter for Molecular Medicine China Medical University and Hospital Taichung TaiwanGraduate Institute of Clinical Medical Science China Medical University Taichung TaiwanGraduate Institute of Clinical Medical Science China Medical University Taichung TaiwanTargeting 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.https://doi.org/10.1002/1878-0261.12102AktclathrinHER2MEKresistance |
spellingShingle | Chia‐Hung Chen Te‐Chun Hsia Ming‐Hsin Yeh Tsung‐Wei Chen Yun‐Ju Chen Jung‐Tsu Chen Ya‐Ling Wei Chih‐Yen Tu Wei‐Chien Huang MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701 Molecular Oncology Akt clathrin HER2 MEK resistance |
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 | Akt clathrin HER2 MEK resistance |
url | https://doi.org/10.1002/1878-0261.12102 |
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