MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701

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.

AS1041, a Novel Synthesized Derivative of Marine Natural Compound Aspergiolide A, Arrests Cell Cycle, Induces Apoptosis, and Inhibits ERK Activation in K562 Cells

“…We hypothesized that AS1041-induced activation of PI3K/AKT/mTOR pathway possibly was also a feedback for the cytotoxicity of AS1041 and inhibition of ERK, and played a protective role against AS1041 damage. Our present work supported the conception that interplays between EKR/AKT oncogenic pathways potentially impact the sensitivity of cancers to their inhibitors [ 43 ]. However, our hypothesis needs furthermore experiments to be proved, for example, combination use of PI3K/AKT/mTOR inhibitors with AS1041 to evaluate whether these inhibitors could increase the efficiency of AS1041.…”

“…This kind of AKT activation was considered to contribute to drug resistance and reduce response to chemotherapeutic agents [ 42 ]. This feedback activation of PI3K/AKT/mTOR is often observed in mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) inhibitor-induced ERK inhibition [ 43 , 44 ]. Feedback activation of PI3K/AKT/mTOR pathway decreases the susceptibility of cancer cells to MEK/ERK inhibition [ 45 , 46 , 47 ].…”

Microscaled proteogenomic methods for precision oncology

“…Of the 21 sites identified, only two have been characterized in detail in cell lines (www.phosphosite.org). These are pY-1248, a known auto-activation site 36 , and pT-701, which may serve as a negative feedback site 37 , although their in-vivo roles are largely unexplored. The role of downregulation of ERBB2 phosphorylation in response to treatment is complicated by the observed downregulation of ERBB2 protein levels, but from a biomarker perspective these are secondary questions that do not negate the primary conclusion that we were able to make a valid pharmacokinetic observation.…”

Microscaled Proteogenomic Methods for Precision Oncology

“…Of the 21 sites identified, only two have been characterized in detail in cell lines (see www.phosphosite.org). These are pY-1248, a known auto-activation site 37 , and pT-701, which may serve as a negative feedback site 38 , although their in-vivo roles are largely unexplored. The role of downregulation of ERBB2 phosphorylation in response to treatment is complicated by the observed downregulation of ERBB2 protein levels, but from a biomarker perspective these are secondary questions that do not negate the primary conclusion that we were able to make a valid pharmacokinetic observation.…”