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

• DOI: 10.1126/sciadv.abh2635
• Publication Date: 2022-01-21T19:00:23Z
• Authors: Jelena Krstic; Isabel Reinisch; Katharina Schindl...; Markus Galhuber; Zina Riahi; Natascha Berger; Nadja Kupper; Elisabeth Moysche...; Martina Auer; Helene Michenthaler; Christoph Nössing; Maria R. Depaoli; Jeta Ramadani-Muja; Sinem Usluer; Sarah Stryeck; Martin Pichler; Beate Rinner; Alexander J. A. D...; Andreas Reinisch; Tobias Madl; Riccardo Zenezini...; Albert J. R. Heck; Meritxell Huch; Roland Malli; Andreas Prokesch
• Keywords: 0301 basic medicine; ddc:610; 03 medical and health sciences; SDG 3 - Good Health and Well-being; Biomedicine and Life Sciences; General; 3. Good health

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 fasting improves sorafenib efficacy acts synergistically sensitize sorafenib-resistant HCC. Mechanistically, noncanonically as an inhibitor of mitochondrial respiration, causing resistant depend on glycolysis for survival. Fasting, through reduction glucose impeded AKT/mTOR signaling, prevents this Warburg shift. Regulating transporter proapoptotic protein expression, p53 is necessary sufficient the sorafenib-sensitizing effect fasting. also crucial fasting-mediated improvement orthotopic HCC mouse model. Together, our data suggest rational combination therapy with intact signaling. As currently severely limited by resistance, these results should instigate clinical studies aimed at improving response advanced-stage