MEK Inhibitors Induce Akt Activation and Drug Resistance by Suppressing Negative Feedback ERK-mediated HER2 Phosphorylation at Thr701

Overview

Journal Mol Oncol

Specialties Molecular Biology
Oncology

Date 2017 Jun 21

PMID 28632938

Citations 36

Authors

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

Affiliations

Soon will be listed here.

Abstract

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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