MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701. Issue 9 (19th July 2017)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Molecular oncology. Volume 11:Issue 9(2017)
• Page Start: 1273
• Page End: 1287
• Publication Date: 2017-07-19
• Subjects: Akt -- clathrin -- HER2 -- MEK -- resistance; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12102
• Languages: English
• ISSNs: 1574-7891

Abstract

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. Abstract : MEK inhibitors suppress ERK‐mediated HER2 Thr701 phosphorylation to enhance clathrin‐dependent HER2/EGFR dimerization and subsequent Akt activation.