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

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Listed:
  • 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
    Harvard Medical School)

  • Kwok-Kin Wong

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Anil K. Rustgi

    (University of Pennsylvania Perelman School of Medicine
    University of Pennsylvania Perelman School of Medicine
    University of Pennsylvania Perelman School of Medicine)

  • J. Alan Diehl

    (Medical University of South Carolina)

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.

Suggested Citation

  • 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, 2019. "Targeting glutamine-addiction and overcoming CDK4/6 inhibitor resistance in human esophageal squamous cell carcinoma," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09179-w
    DOI: 10.1038/s41467-019-09179-w
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