ArticleMolecular oncology2023
Activation of the EGFR/PI3K/AKT pathway limits the efficacy of trametinib treatment in head and neck cancer.
Article in Molecular oncology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 30 citations in OpenAlex.
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- Unraveling the molecular landscape: an overview on gene expression, epigenetic alterations, and therapeutic challenges in head and neck squamous cell carcinoma.Molecular genetics and genomics : MGG · 2026Review
- Molecular Mechanisms in Oral Squamous Cell Carcinoma: Integrative Roles of Cancer-Associated Fibroblasts, Immune Microenvironment, and Precision Therapeutic Opportunities.International journal of molecular sciences · 2026Review
- LCP1 upregulation via EGFR signaling promotes oral cancer progression through the JAK2/STAT3/IL-1β axis.Cancer cell international · 2025Article
- Paxilline derived from an endophytic fungus of Baphicacanthus cusia alleviates hepatocellular carcinoma through autophagy-mediated apoptosis.Scientific reports · 2025Article
- Dual Disruption of EGFR/PI3K Signaling: IGF2BP2 Targeting Reverses Anti-EGFR Resistance in CAFs-Infiltrated Oral Squamous Cell Carcinoma.International journal of molecular sciences · 2025Article
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- Personalized Treatment Strategies via Integration of Gene Expression Biomarkers in Molecular Profiling of Laryngeal Cancer.Journal of personalized medicine · 2024Review
- From Tyrosine Kinases to Tyrosine Phosphatases: New Therapeutic Targets in Cancers and Beyond.Pharmaceutics · 2024Review
- The combination of breast cancer PDO and mini-PDX platform for drug screening and individualized treatment.Journal of cellular and molecular medicine · 2024Article
- Gentiopicroside inhibits the progression of gastric cancer through modulating EGFR/PI3K/AKT signaling pathway.European journal of medical research · 2024Article
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Authors and funding
18 authors at 5 institutions in 5 countries.
Funding
Abstract
Blocking the mitogen-activated protein kinase (MAPK) pathway with the MEK1/2 inhibitor trametinib has produced promising results in patients with head and neck squamous cell carcinoma (HNSCC). In the current study, we showed that trametinib treatment leads to overexpression and activation of the epidermal growth factor receptor (EGFR) in HNSCC cell lines and patient-derived xenografts. Knockdown of EGFR improved trametinib treatment efficacy both in vitro and in vivo. Mechanistically, we demonstrated that trametinib-induced EGFR overexpression hyperactivates the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. In vitro, blocking the PI3K pathway with GDC-0941 (pictilisib), or BYL719 (alpelisib), prevented AKT pathway hyperactivation and enhanced the efficacy of trametinib in a synergistic manner. In vivo, a combination of trametinib and BYL719 showed superior antitumor efficacy vs. the single agents, leading to tumor growth arrest. We confirmed our findings in a syngeneic murine head and neck cancer cell line in vitro and in vivo. Taken together, our findings show that trametinib treatment induces hyperactivation of EGFR/PI3K/AKT; thus, blocking of the EGFR/PI3K pathway is required to improve trametinib efficacy in HNSCC.
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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 Socratic graph.