Fasting reverses drug-resistance in hepatocellular carcinoma through p53-dependent metabolic synergism

Cancer cells voraciously consume nutrients to support their growth, exposing a metabolic vulnerability that can be therapeutically exploited. Here we show in hepatocellular carcinoma (HCC) cells, xenografts, and in patient-derived HCC organoids that fasting can synergistically sensitize resistant HCC to sorafenib. Mechanistically, sorafenib acts non-canonically 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 pro-apoptotic 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 intermittent 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, and possibly even early-stage, HCC.HIGHLIGHTSFasting sensitizes resistant HCC xenografts and patient-derived organoids to sorafenibSorafenib-mediated Warburg shift is prevented by glucose limitation upon fastingFasting synergistically improves sorafenib efficacy in non-resistant modelsp53 is required for synergism by regulating glucose uptake and apoptosisGRAPHICAL ABSTRACT