ArticleCancer research2012
MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors.
Article in Cancer research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 232 papers, 2 of them syntheses that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
232 citing papers in PubMed, 2 syntheses or guidelines pooled it, 358 citations in OpenAlex.
- A comprehensive overview of the molecular features and therapeutic targets in BRAFClinical and translational medicine · 2024Pooled it
- Updated guidelines for biomarker testing in colorectal carcinoma: a national consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2015Guideline
- Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial.JAMA oncology · 2017Trial
- Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer.Investigational new drugs · 2015Trial
- MEK Inhibitors and Toll-like Receptor Signaling: Implications for Infection and Inflammation.International journal of molecular sciences · 2026Review
- Decreased PP2A expression and activity represent a therapeutic target for plexiform neurofibroma.Acta neuropathologica communications · 2026Article
- Colorectal cancer cells respond differentially to autophagy induced by tyrosine kinase inhibitors.Scientific reports · 2026Article
- Chronic activation of p38α in skeletal muscle causes necrotic changes, but also abolishes expression of MK2, MK3, and MKK6 and the muscle recovers.The Journal of biological chemistry · 2026Article
- Article
- Pan-RAF inhibitor exarafenib targets BRAF class II/III NSCLC and reveals ARAF-KSR1 resistance and combination strategies.Nature communications · 2026Article
- Temozolomide increases the generation of cell heterogeneity in ERK activity in glioma cells.Journal of molecular medicine (Berlin, Germany) · 2026Article
- Phosphatidylinositol-3-Kinase (PI3K) and Histone Deacetylase (HDAC) Multitarget Inhibitors: An Update on Clinical and Preclinical Candidates.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Bracing for the storm: emerging resistance mechanisms to KRAS inhibitors in pancreatic cancer and strategies to overcome them.Cancer drug resistance (Alhambra, Calif.) · 2026Review
- Integrin-linked kinase (ILK) in hematologic malignancies: Bridging molecular mechanisms to therapeutic innovation.BioImpacts : BI · 2026Review
- Harnessing transcriptomics for discovery of natural products to overcome acquired cancer resistance.Archives of pharmacal research · 2026Review
- KRAS Codon-Specific Mutations Differentially Toggle PI3K Pathway Signaling and Alter Sensitivity to Inavolisib (GDC-0077).Molecular cancer therapeutics · 2025Article
- Targeting KRAS mutations: orchestrating cancer evolution and therapeutic challenges.Signal transduction and targeted therapy · 2025Review
- Targeting BRAF Class II and III Mutations in NSCLC with the pan-RAF inhibitor Exarafenib Reveals ARAF-KSR1-Mediated Resistance and Rational Combination Strategies.Research square · 2025Article
- RAS Pathway Inhibitors Combined with Targeted Agents Are Active in Patient-Derived Spheroids with Oncogenic KRAS Variants from Multiple Cancer Types.Cancer research communications · 2025Article
- Wild-type RAS signaling is an essential therapeutic target inScience signaling · 2025Article
172 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
The phosphoinositide 3-kinase (PI3K)/AKT and RAF/MEK/ERK signaling pathways are activated in a wide range of human cancers. In many cases, concomitant inhibition of both pathways is necessary to block proliferation and induce cell death and tumor shrinkage. Several feedback systems have been described in which inhibition of one intracellular pathway leads to activation of a parallel signaling pathway, thereby decreasing the effectiveness of single-agent targeted therapies. In this study, we describe a feedback mechanism in which MEK inhibition leads to activation of PI3K/AKT signaling in EGFR and HER2-driven cancers. We found that MEK inhibitor-induced activation of PI3K/AKT resulted from hyperactivation of ERBB3 as a result of the loss of an inhibitory threonine phosphorylation in the conserved juxtamembrane domains of EGFR and HER2. Mutation of this amino acid led to increased ERBB receptor activation and upregulation of the ERBB3/PI3K/AKT signaling pathway, which was no longer responsive to MEK inhibition. Taken together, these results elucidate an important, dominant feedback network regulating central oncogenic pathways in human cancer.
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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.