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GLUT1 inhibition blocks growth of RB1-positive triple negative breast cancer

Qin Wu1,2,3, Wail Ba-Alawi2,3, Genevieve Deblois2

  • 1Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.

Nature Communications
|August 23, 2020
PubMed

Insights

Triple negative breast cancer (TNBC) cells with high glycolysis show vulnerability to glucose transporter 1 (GLUT1) inhibition. Retinoblastoma protein 1 (RB1) levels predict sensitivity, highlighting a targetable RB1-GLUT1 axis for new TNBC therapeutics.

Area of Science:

  • Oncology
  • Metabolic Pathways
  • Molecular Biology

Background:

  • Triple negative breast cancer (TNBC) presents a significant clinical challenge due to chemotherapy resistance in over 30% of patients.
  • Elevated glucose transporter 1 (GLUT1) expression and metabolic reprogramming are characteristic of TNBC, suggesting potential therapeutic vulnerabilities.
  • There is an urgent need for novel therapeutics and companion biomarkers for TNBC treatment.

Purpose of the Study:

  • To investigate the therapeutic potential of inhibiting glucose transporter 1 (GLUT1) in triple negative breast cancer (TNBC).
  • To identify biomarkers that predict sensitivity to GLUT1 inhibition in TNBC.
  • To explore the metabolic dependencies and regulatory pathways associated with GLUT1 function in TNBC.

Main Methods:

  • Utilized genetic and pharmacological inhibition of GLUT1 using BAY-876 in TNBC cell lines and patient-derived samples.
  • Assessed TNBC cell growth inhibition in response to GLUT1 targeting.
  • Performed gene expression analysis and pathway enrichment analysis (e.g., E2F pathway).
  • Correlated retinoblastoma tumor suppressor (RB1) protein levels with sensitivity to GLUT1 inhibition.

Main Results:

  • GLUT1 inhibition, via genetic or pharmacological means, impaired the growth of a subset of TNBC cells.
  • Sensitivity to GLUT1 inhibition was observed in TNBC cells with high glycolytic rates and lower oxidative phosphorylation (OXPHOS).
  • Retinoblastoma tumor suppressor (RB1) protein levels strongly correlated with sensitivity; RB1-negative cells were insensitive to GLUT1 inhibition.
  • E2F pathway activity showed a potential correlation with OXPHOS activity.

Conclusions:

  • A targetable metabolic axis involving RB1 and GLUT1 exists in TNBC.
  • RB1 protein expression can serve as a predictive biomarker for response to GLUT1 inhibition in TNBC.
  • Clinical evaluation of GLUT1 inhibitors in RB1-stratified TNBC patient populations is warranted.

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