ArticleMolecular oncology2017
MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK-mediated HER2 phosphorylation at Thr701.
Article in Molecular oncology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 60 citations in OpenAlex.
- Selumetinib in adults with NF1 and inoperable plexiform neurofibroma: a phase 2 trial.Nature medicine · 2025Trial
- Targeting Activated Pathways in Doxorubicin-Resistant TNBC Alters Signaling, Survival and EMT: A Double-Edged Sword.International journal of molecular sciences · 2026Article
- Phosphorylation-dependent regulation of Eleven Lysine Rich Leukemia (ELL) uncovered by quantitative global phosphoproteomic analysis.Molecular genetics and genomics : MGG · 2026Article
- Selumetinib in Adult Neurofibromatosis 1 with Plexiform Neurofibroma.Pharmaceuticals (Basel, Switzerland) · 2025Article
- ERK1/2 Signaling in Intrahepatic Cholangiocarcinoma: From Preclinical Advances to Therapeutic Strategies.Biology · 2025Review
- Role of histone-lysine N-methyltransferase 2D (KMT2D) in MEK-ERK signaling-mediated epigenetic regulation: a phosphoproteomics perspective.Frontiers in bioinformatics · 2025Article
- Chronic Kidney Disease-associated Lung Injury Is Mediated by Phosphate-induced MAPK/AKT Signaling.American journal of respiratory cell and molecular biology · 2024Article
- Quantitative systems pharmacology modeling of HER2-positive metastatic breast cancer for translational efficacy evaluation and combination assessment across therapeutic modalities.Acta pharmacologica Sinica · 2024Article
- Targeting solid tumor antigens with chimeric receptors: cancer biology meets synthetic immunology.Trends in cancer · 2024Review
- Blocking of doublecortin-like kinase 1-regulated SARS-CoV-2 replication cycle restores cell signaling network.Journal of virology · 2023Article
- A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma.Cancer gene therapy · 2023Article
- Integrated Transcriptome and Molecular Docking to Identify the Hub Superimposed Attenuation Targets of Curcumin in Breast Cancer Cells.International journal of molecular sciences · 2023Article
- Salivary gland cancer organoids are valid for preclinical genotype-oriented medical precision trials.iScience · 2023Article
- Opportunities and Obstacles to the Development of Health Data Warehouses in Hospitals in France: The Recent Experience of Comprehensive Cancer Centers.International journal of environmental research and public health · 2023Review
- Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function.Frontiers in cell and developmental biology · 2023Article
- A preclinical model of patient-derived cerebrospinal fluid circulating tumor cells for experimental therapeutics in leptomeningeal disease from melanoma.Neuro-oncology · 2022Article
- PSMG2-controlled proteasome-autophagy balance mediates the tolerance for MEK-targeted therapy in triple-negative breast cancer.Cell reports. Medicine · 2022Article
- Co-Targeting MAP Kinase and Pi3K-Akt-mTOR Pathways in Meningioma: Preclinical Study of Alpelisib and Trametinib.Cancers · 2022Article
- Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models.Frontiers in oncology · 2022Article
- Jagged-1 is induced by mTOR inhibitors in renal cancer cells through an Akt/ALK5/Smad4-dependent mechanism.Current research in pharmacology and drug discovery · 2022Article
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.