ArticleJCI insight2019
Rational combination with PDK1 inhibition overcomes cetuximab resistance in head and neck squamous cell carcinoma.
Article in JCI insight, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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
17 citing papers in PubMed, 34 citations in OpenAlex.
- The role of the tumor microenvironment in HNSCC resistance and targeted therapy.Frontiers in immunology · 2025Review
- Novel insights from comprehensive analysis: The role of cuproptosis and peripheral immune infiltration in Alzheimer's disease.PloS one · 2025Article
- The tumor ecosystem in head and neck squamous cell carcinoma and advances in ecotherapy.Molecular cancer · 2023Review
- Andrographolide suppresses aerobic glycolysis and induces apoptotic cell death by inhibiting pyruvate dehydrogenase kinase 1 expression.Oncology reports · 2023Article
- PDK1- and PDK2-mediated metabolic reprogramming contributes to the TGFβ1-promoted stem-like properties in head and neck cancer.Cancer & metabolism · 2022Article
- Analysis of the epidermal growth factor receptor/phosphoinositide-dependent protein kinase-1 axis in tumor of the external auditory canal in response to epidermal growth factor stimulation.Laryngoscope investigative otolaryngology · 2022Article
- Review
- Glutamine metabolism in cancers: Targeting the oxidative homeostasis.Frontiers in oncology · 2022Review
- Angiogenic activities are increased via upregulation of HIF-1α expression in gefitinib-resistant non-small cell lung carcinoma cells.Oncology letters · 2021Article
- Altered glycolysis results in drug-resistant in clinical tumor therapy.Oncology letters · 2021Review
- Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines.BMC cancer · 2021Article
- DMP-1 promoter-associated antisense strand non-coding RNA, panRNA-DMP-1, physically associates with EGFR to repress EGF-induced squamous cell carcinoma migration.Molecular and cellular biochemistry · 2021Article
- Oxidative Stress and the Intersection of Oncogenic Signaling and Metabolism in Squamous Cell Carcinomas.Cells · 2021Review
- Article
- Computational Identification of Stearic Acid as a Potential PDK1 Inhibitor and In Vitro Validation of Stearic Acid as Colon Cancer Therapeutic in Combination with 5-Fluorouracil.Cancer informatics · 2021Article
- Precision Medicine Approaches to Overcome Resistance to Therapy in Head and Neck Cancers.Frontiers in oncology · 2021Review
- Mechanisms of resistance in head and neck cancer.American journal of cancer research · 2020Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Cetuximab, an EGFR-blocking antibody, is currently approved for treatment of metastatic head and neck squamous cell carcinoma (HNSCC), but its response rate is limited. In addition to blocking EGFR-stimulated cell signaling, cetuximab can induce endocytosis of ASCT2, a glutamine transporter associated with EGFR in a complex, leading to glutathione biosynthesis inhibition and cellular sensitization to ROS. Pyruvate dehydrogenase kinase-1 (PDK1), a key mitochondrial enzyme overexpressed in cancer cells, redirects glucose metabolism from oxidative phosphorylation toward aerobic glycolysis. In this study, we tested the hypothesis that targeting PDK1 is a rational approach to synergize with cetuximab through ROS overproduction. We found that combination of PDK1 knockdown or inhibition by dichloroacetic acid (DCA) with ASCT2 knockdown or with cetuximab treatment induced ROS overproduction and apoptosis in HNSCC cells, and this effect was independent of effective inhibition of EGFR downstream pathways but could be lessened by N-acetyl cysteine, an anti-oxidative agent. In several cetuximab-resistant HNSCC xenograft models, DCA plus cetuximab induced marked tumor regression, whereas either agent alone failed to induce tumor regression. Our findings call for potentially novel clinical trials of combining cetuximab and DCA in patients with cetuximab-sensitive EGFR-overexpressing tumors and patients with cetuximab-resistant EGFR-overexpressing tumors.
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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.