Nature communications, 2019-03, Vol.10 (1), p.1296-15, Article 1296
2019
Details
- Autor(en) / Beteiligte
- Titel
- Targeting glutamine-addiction and overcoming CDK4/6 inhibitor resistance in human esophageal squamous cell carcinoma
- Ist Teil von
- Nature communications, 2019-03, Vol.10 (1), p.1296-15, Article 1296
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- The dysregulation of Fbxo4-cyclin D1 axis occurs at high frequency in esophageal squamous cell carcinoma (ESCC), where it promotes ESCC development and progression. However, defining a therapeutic vulnerability that results from this dysregulation has remained elusive. Here we demonstrate that Rb and mTORC1 contribute to Gln-addiction upon the dysregulation of the Fbxo4-cyclin D1 axis, which leads to the reprogramming of cellular metabolism. This reprogramming is characterized by reduced energy production and increased sensitivity of ESCC cells to combined treatment with CB-839 (glutaminase 1 inhibitor) plus metformin/phenformin. Of additional importance, this combined treatment has potent efficacy in ESCC cells with acquired resistance to CDK4/6 inhibitors in vitro and in xenograft tumors. Our findings reveal a molecular basis for cancer therapy through targeting glutaminolysis and mitochondrial respiration in ESCC with dysregulated Fbxo4-cyclin D1 axis as well as cancers resistant to CDK4/6 inhibitors.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-019-09179-wTitel-ID: cdi_doaj_primary_oai_doaj_org_article_1faab1692f4b47f8a3c1390b1123f127
- Format
- –
- Schlagworte
- Addiction, Animals, Antineoplastic Agents - pharmacology, Benzeneacetamides - pharmacology, Cell Line, Tumor, Cellular manufacture, Combined treatment, Cyclin D1, Cyclin D1 - genetics, Cyclin D1 - metabolism, Cyclin-dependent kinase 4, Cyclin-Dependent Kinase 4 - antagonists & inhibitors, Cyclin-Dependent Kinase 4 - genetics, Cyclin-Dependent Kinase 4 - metabolism, Cyclin-Dependent Kinase 6 - antagonists & inhibitors, Cyclin-Dependent Kinase 6 - genetics, Cyclin-Dependent Kinase 6 - metabolism, Drug Resistance, Neoplasm - drug effects, Drug Resistance, Neoplasm - genetics, Drug Synergism, Electron transport, Energy Metabolism - drug effects, Energy Metabolism - genetics, Esophageal Neoplasms - drug therapy, Esophageal Neoplasms - genetics, Esophageal Neoplasms - metabolism, Esophageal Neoplasms - pathology, Esophageal Squamous Cell Carcinoma - drug therapy, Esophageal Squamous Cell Carcinoma - genetics, Esophageal Squamous Cell Carcinoma - metabolism, Esophageal Squamous Cell Carcinoma - pathology, Esophagus, F-Box Proteins - genetics, F-Box Proteins - metabolism, Gene Expression Regulation, Neoplastic, Glutaminase, Glutaminase - antagonists & inhibitors, Glutaminase - genetics, Glutaminase - metabolism, Glutamine, Glutamine - antagonists & inhibitors, Glutamine - metabolism, Humans, Hypoglycemic Agents - pharmacology, Inhibitors, Male, Mechanistic Target of Rapamycin Complex 1 - genetics, Mechanistic Target of Rapamycin Complex 1 - metabolism, Metabolism, Metformin, Metformin - pharmacology, Mice, Mitochondria, Molecular Targeted Therapy, Phenformin - pharmacology, Protein Kinase Inhibitors - pharmacology, Retinoblastoma Protein - genetics, Retinoblastoma Protein - metabolism, Signal Transduction, Squamous cell carcinoma, Thiadiazoles - pharmacology, Tumors, Xenograft Model Antitumor Assays, Xenografts, Xenotransplantation