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. HIGHLIGHTSO_LIFasting sensitizes resistant HCC xenografts and patient-derived organoids to sorafenib C_LIO_LISorafenib-mediated Warburg shift is prevented by glucose limitation upon fasting C_LIO_LIFasting synergistically improves sorafenib efficacy in non-resistant models C_LIO_LIp53 is required for synergism by regulating glucose uptake and apoptosis C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/430545v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1c0bf9org.highwire.dtl.DTLVardef@15638b4org.highwire.dtl.DTLVardef@1a4b322org.highwire.dtl.DTLVardef@1ec863a_HPS_FORMAT_FIGEXP M_FIG C_FIG