2. Academic Validation
  3. Fasting improves therapeutic response in hepatocellular carcinoma through p53-dependent metabolic synergism

Fasting improves therapeutic response in hepatocellular carcinoma through p53-dependent metabolic synergism

  • Sci Adv. 2022 Jan 21;8(3):eabh2635. doi: 10.1126/sciadv.abh2635.
Jelena Krstic 1,  Isabel Reinisch 1,  Katharina Schindlmaier 1,  Markus Galhuber 1,  Zina Riahi 1,  Natascha Berger 1 2,  Nadja Kupper 1,  Elisabeth Moyschewitz 1,  Martina Auer 1,  Helene Michenthaler 1,  Christoph Nössing 1 3,  Maria R Depaoli 4,  Jeta Ramadani-Muja 4,  Sinem Usluer 4,  Sarah Stryeck 4 5 6,  Martin Pichler 7,  Beate Rinner 8,  Alexander J A Deutsch 9,  Andreas Reinisch 9 10,  Tobias Madl 4 11,  Riccardo Zenezini Chiozzi 12 13,  Albert J R Heck 12 13,  Meritxell Huch 14,  Roland Malli 4 11,  Andreas Prokesch 1 11
Affiliations

Affiliations

  • 1 Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, 8010 Graz, Austria.
  • 2 Department of Obstetrics and Gynecology, Medical University of Graz, 8036 Graz, Austria.
  • 3 Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK.
  • 4 Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria.
  • 5 Institute of Interactive Systems and Data Science, Graz University of Technology, 8010 Graz, Austria.
  • 6 Know-Center GmbH, 8010 Graz, Austria.
  • 7 Division of Clinical Oncology, Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, 8036 Graz, Austria.
  • 8 Department for Biomedical Research, Medical University of Graz, Graz, Austria.
  • 9 Division of Hematology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.
  • 10 Division of Hematology, Department of Blood Group Serology and Transfusion Medicine Medical University of Graz, 8036 Graz, Austria.
  • 11 BioTechMed-Graz, 8010 Graz, Austria.
  • 12 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute of Pharmaceutical Sciences, Utrecht University, 3584CH Utrecht, Netherlands.
  • 13 Netherlands Proteomics Center, 3584CH Utrecht, Netherlands.
  • 14 Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
PMID: 35061544 DOI: 10.1126/sciadv.abh2635
Abstract

Cancer cells voraciously consume nutrients to support their growth, exposing metabolic vulnerabilities that can be therapeutically exploited. Here, we show in hepatocellular carcinoma (HCC) cells, xenografts, and patient-derived organoids that fasting improves sorafenib efficacy and acts synergistically to sensitize sorafenib-resistant HCC. Mechanistically, sorafenib acts noncanonically as an inhibitor of mitochondrial respiration, causing resistant cells to depend on glycolysis for survival. Fasting, through reduction in glucose and impeded Akt/mTOR signaling, prevents this Warburg shift. Regulating glucose transporter and proapoptotic protein expression, p53 is necessary and sufficient for the sorafenib-sensitizing effect of fasting. p53 is also crucial for fasting-mediated improvement of sorafenib efficacy in an orthotopic HCC mouse model. Together, our data suggest fasting and sorafenib as rational combination therapy for HCC with intact p53 signaling. As HCC therapy is currently severely limited by resistance, these results should instigate clinical studies aimed at improving therapy response in advanced-stage HCC.

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