Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Animals
-
Antineoplastic Agents / pharmacology*
-
Benzeneacetamides / pharmacology
-
Cell Line, Tumor
-
Cyclin D1 / genetics
-
Cyclin D1 / metabolism
-
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
-
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
-
F-Box Proteins / genetics
-
F-Box Proteins / metabolism
-
Gene Expression Regulation, Neoplastic*
-
Glutaminase / antagonists & inhibitors
-
Glutaminase / genetics
-
Glutaminase / metabolism
-
Glutamine / antagonists & inhibitors
-
Glutamine / metabolism*
-
Humans
-
Hypoglycemic Agents / pharmacology*
-
Male
-
Mechanistic Target of Rapamycin Complex 1 / genetics
-
Mechanistic Target of Rapamycin Complex 1 / metabolism
-
Metformin / pharmacology
-
Mice
-
Molecular Targeted Therapy
-
Phenformin / pharmacology
-
Protein Kinase Inhibitors / pharmacology*
-
Retinoblastoma Protein / genetics
-
Retinoblastoma Protein / metabolism
-
Signal Transduction
-
Thiadiazoles / pharmacology
-
Xenograft Model Antitumor Assays
Substances
-
Antineoplastic Agents
-
Benzeneacetamides
-
CB-839
-
CCND1 protein, human
-
F-Box Proteins
-
FBXO4 protein, human
-
Hypoglycemic Agents
-
Protein Kinase Inhibitors
-
Retinoblastoma Protein
-
Thiadiazoles
-
Glutamine
-
Cyclin D1
-
Metformin
-
Phenformin
-
Mechanistic Target of Rapamycin Complex 1
-
CDK4 protein, human
-
CDK6 protein, human
-
Cyclin-Dependent Kinase 4
-
Cyclin-Dependent Kinase 6
-
Glutaminase