Open AccessMEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK ‐mediated HER 2 phosphorylation at Thr701
Author(s) -
Chen ChiaHung,
Hsia TeChun,
Yeh MingHsin,
Chen TsungWei,
Chen YunJu,
Chen JungTsu,
Wei YaLing,
Tu ChihYen,
Huang WeiChien
Publication year - 2017
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12102
Subject(s) - protein kinase b , phosphorylation , mapk/erk pathway , pi3k/akt/mtor pathway , chemistry , mek inhibitor , microbiology and biotechnology , kinase , cancer research , signal transduction , biology
Targeting the MEK / ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI 3K/ 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 HER 2‐positive breast cancer cells. Silence of HER 2, or overexpression of HER 2 kinase‐dead mutant, prevents the induction of Akt activation in response to MEK inhibition, indicating HER 2 as a critical regulator for this event. Furthermore, HER 2 Thr701 was demonstrated as a direct phosphorylation target of ERK 1/2. Inhibition of this specific phosphorylation prolonged the dimerization of HER 2 with EGFR in a clathrin‐dependent manner, leading to the enhanced activation of HER 2 and EGFR tyrosine kinase and their downstream Akt pathway. These results suggest that suppression of ERK ‐mediated HER 2 Thr701 phosphorylation contributes to MEK inhibitor‐induced Akt activation.