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. 2019 May 7;6(4):1610257.
doi: 10.1080/23723556.2019.1610257. eCollection 2019.

Glutamine addiction: an Achilles heel in esophageal cancers with dysregulation of CDK4/6

Shuo Qie  1 , J Alan Diehl  1
Affiliations

Glutamine addiction: an Achilles heel in esophageal cancers with dysregulation of CDK4/6

Shuo Qie et al. Mol Cell Oncol. .

Abstract

Understanding and overcoming resistance to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors will be challenging. Recent work reveals that dysregulation of F-Box Protein 4 (FBXO4)-Cyclin D1 axis leads to mitochondrial dysfunction and drives glutamine-addiction in esophageal squamous cell carcinoma. This metabolism feature makes these tumors susceptible to combined treatment with glutaminase (GLS) inhibitor and metformin even when resisting to CDK4/6 inhibitors.

Keywords: CDK4/6 inhibitor; Glutamine-addiction; acquired resistance; cyclin D1; glutaminase.

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Figures

Figure 1.
Figure 1.
Molecular mechanisms of combined treatment with CB-839 and metformin/phenformin. 1) Loss of function mutations in F-Box Protein 4 (FBXO4) or hyperactivation of the Cyclin D1 (CCND1)-cyclin-dependent kinase 4/6 (CDK4/6) leads to mitochondrial dysfunction and glutamine-addiction. Taking advantage of these metabolism characteristics, targeting both glutaminase (GLS) and oxidative phosphorylation (OXPHOS) causes the imbalance between energy production and consumption, thereafter, energetic catastrophe, and finally cell death. 2) Palbociclib-resistant cells demonstrate RB transcriptional corepressor 1 (RB) loss that drives glutamine-addiction; moreover, these cells are more sensitive to combined treatment when compared with their parental counterparts. ESCC: esophageal squamous cell carcinoma.
See this image and copyright information in PMC

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