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Fasting-mimicking diet blocks triple-negative breast cancer and cancer stem cell escape

Giulia Salvadori1, Federica Zanardi2, Fabio Iannelli2

  • 1University of Milan, Department of Oncology and Hemato-oncology, Milan 20122, Italy; IFOM, FIRC Institute of Molecular Oncology, Milan 20139, Italy.

Cell Metabolism
|November 3, 2021
PubMed

Insights

A fasting-mimicking diet (FMD) targets cancer stem cells and enhances therapy for metastatic triple-negative breast cancer (TNBC). FMD reduces cancer cell repopulation and improves survival by modulating key signaling pathways.

Area of Science:

  • Oncology
  • Metabolic Therapies
  • Cancer Stem Cell Biology

Background:

  • Metastatic tumors are a leading cause of cancer mortality, often driven by therapeutic resistance and cancer stem cell (CSC) repopulation.
  • Triple-negative breast cancer (TNBC) presents significant treatment challenges due to its aggressive nature and lack of targeted therapies.

Purpose of the Study:

  • To investigate the effects of a fasting-mimicking diet (FMD) on cancer stem cells (CSCs) and differentiated cancer cells in metastatic TNBC.
  • To identify and target starvation escape pathways activated by FMD in cancer cells for therapeutic benefit.
  • To evaluate the potential of FMD in combination with other therapies to overcome treatment resistance and improve patient survival.

Main Methods:

  • Administration of a fasting-mimicking diet (FMD) to preclinical models of metastatic TNBC.
  • Analysis of key signaling pathways, including glucose-dependent protein kinase A, PI3K-AKT, mTOR, and CDK4/6, in cancer cells and CSCs.
  • Assessment of stemness markers, cell proliferation, and survival rates in response to FMD.
  • Correlation of patient glycemia levels with survival outcomes in metastatic TNBC.

Main Results:

  • FMD activates starvation escape pathways in TNBC cells, enabling identification and targeting by drugs.
  • In CSCs, FMD reduces stemness markers and cell number by lowering glucose-dependent protein kinase A signaling, increasing mouse survival.
  • In differentiated cancer cells, FMD activates PI3K-AKT, mTOR, and CDK4/6 pathways, which can be targeted for tumor regression.
  • FMD cycles mitigate hyperglycemia and toxicities associated with targeted cancer therapies.

Conclusions:

  • Fasting-mimicking diet (FMD) exhibits differential effects on normal, cancer, and cancer stem cells.
  • FMD facilitates the identification and targeting of starvation escape pathways, offering a potential therapeutic strategy for various malignancies.
  • Combining FMD with targeted therapies may enhance treatment efficacy and reduce toxicity in metastatic TNBC patients.
Keywords:
CDK4/6PI3K/AKTPKAcancer stem cellsfastingfasting-mimicking dietglucosemTORstarvation escape pathwaystriple-negative breast cancer

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