2. Academic Validation
  3. Fasting-mimicking diet blocks triple-negative breast cancer and cancer stem cell escape

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

  • Cell Metab. 2021 Nov 2;33(11):2247-2259.e6. doi: 10.1016/j.cmet.2021.10.008.
Giulia Salvadori 1,  Federica Zanardi 2,  Fabio Iannelli 2,  Riccardo Lobefaro 3,  Claudio Vernieri 4,  Valter D Longo 5
Affiliations

Affiliations

  • 1 University of Milan, Department of Oncology and Hemato-oncology, Milan 20122, Italy; IFOM, FIRC Institute of Molecular Oncology, Milan 20139, Italy.
  • 2 IFOM, FIRC Institute of Molecular Oncology, Milan 20139, Italy.
  • 3 Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy.
  • 4 IFOM, FIRC Institute of Molecular Oncology, Milan 20139, Italy; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy.
  • 5 IFOM, FIRC Institute of Molecular Oncology, Milan 20139, Italy; Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: vlongo@usc.edu.
PMID: 34731655 DOI: 10.1016/j.cmet.2021.10.008
Abstract

Metastatic tumors remain lethal due to primary/acquired resistance to therapy or Cancer stem cell (CSC)-mediated repopulation. We show that a fasting-mimicking diet (FMD) activates starvation escape pathways in triple-negative breast Cancer (TNBC) cells, which can be identified and targeted by drugs. In CSCs, FMD lowers glucose-dependent protein kinase A signaling and stemness markers to reduce cell number and increase mouse survival. Accordingly, metastatic TNBC patients with lower glycemia survive longer than those with higher baseline glycemia. By contrast, in differentiated Cancer cells, FMD activates PI3K-AKT, mTOR, and CDK4/6 as survival/growth pathways, which can be targeted by drugs to promote tumor regression. FMD cycles also prevent hyperglycemia and Other toxicities caused by these drugs. These data indicate that FMD has wide and differential effects on normal, Cancer, and CSCs, allowing the rapid identification and targeting of starvation escape pathways and providing a method potentially applicable to many malignancies.

Keywords

CDK4/6; PI3K/AKT; PKA; cancer stem cells; fasting; fasting-mimicking diet; glucose; mTOR; starvation escape pathways; triple-negative breast cancer.

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