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

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 and J. Alan Diehl ()
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Shuo Qie: Medical University of South Carolina
Akihiro Yoshida: Medical University of South Carolina
Stuart Parnham: Medical University of South Carolina
Natalia Oleinik: Medical University of South Carolina
Gyda C. Beeson: Medical University of South Carolina
Craig C. Beeson: Medical University of South Carolina
Besim Ogretmen: Medical University of South Carolina
Adam J. Bass: Dana-Farber Cancer Institute
Kwok-Kin Wong: Dana-Farber Cancer Institute
Anil K. Rustgi: University of Pennsylvania Perelman School of Medicine
J. Alan Diehl: Medical University of South Carolina

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09179-w

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