Targeting glutamine-addiction and overcoming CDK4/6 inhibitor resistance in human esophageal squamous cell carcinoma.

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.

• Authors: Shuo Qie, Akihiro Yoshida, Stuart Parnham, Natalia Oleinik, Gyda C Beeson, Craig C Beeson, Besim Ogretmen, Adam J Bass, Kwok-Kin Wong, Anil K Rustgi, J Alan Diehl
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 1296 (03 21 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 30899002 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 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

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Benzeneacetamides (pharmacology)
• Cell Line, Tumor
• Cyclin D1 (genetics, metabolism)
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors, genetics, metabolism)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors, genetics, metabolism)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Drug Synergism
• Energy Metabolism (drug effects, genetics)
• Esophageal Neoplasms (drug therapy, genetics, metabolism, pathology)
• Esophageal Squamous Cell Carcinoma (drug therapy, genetics, metabolism, pathology)
• F-Box Proteins (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Glutaminase (antagonists & inhibitors, genetics, metabolism)
• Glutamine (antagonists & inhibitors, metabolism)
• Humans
• Hypoglycemic Agents (pharmacology)
• Male
• Mechanistic Target of Rapamycin Complex 1 (genetics, metabolism)
• Metformin (pharmacology)
• Mice
• Molecular Targeted Therapy
• Phenformin (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Retinoblastoma Protein (genetics, metabolism)
• Signal Transduction
• Thiadiazoles (pharmacology)
• Xenograft Model Antitumor Assays