Journal
SCIENCE ADVANCES
Volume 8, Issue 3, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abh2635
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Funding
- Austrian Science Fund (FWF) [I3165, P29328, P34109]
- Oesterreichische Nationalbank (Austrian Central Bank, Anniversary Fund) [18517]
- MEFOgraz research grant
- PhD faculty MolMed at the Medical University of Graz
- MEFOgraz grant from the Medical University of Graz
- Horizon 2020 program of the European Union [0000260]
- Austrian Science Foundation [P28854, I3792, DK-MCD W1226]
- Austrian Research Promotion Agency (FFG) [864690, 870454]
- Integrative Metabolism Research Center Graz
- Austrian Infrastructure Program 2016/2017
- Styrian Government (Zukunftsfonds)
- BioTechMed-Graz (Flagship project)
- Austrian Science Fund (FWF) [P34109, I3165, P29328] Funding Source: Austrian Science Fund (FWF)
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Fasting improves the efficacy of sorafenib and sensitizes sorafenib-resistant HCC by preventing the Warburg shift through reduction in glucose and AKT/mTOR signaling. p53 is necessary for the sorafenib-sensitizing effect of fasting.
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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