Tumour metabolism in squamous cell carcinoma of the head and neck: an in-vitro study of the consequences of TP53 mutation and therapeutic implications

Abstract

BackgroundSurvival for squamous cell carcinoma of the head and neck (SCCHN) has not improved substantially in recent years. Since radiotherapy is a cornerstone of treatment, it is crucial to identify ways to augment its efficacy, for which tumour metabolism is an attractive target. p53 is a metabolic mediator, and TP53 mutations are common in this disorder. We sought to investigate metabolic changes in SCCHN, to elucidate any correlation with TP53 status, and to determine whether targeted metabolic therapy might be used to potentiate the effects of radiation. MethodsExtracellular acidification and oxygen consumptions rates, respective measures of glycolytic flux and mitochondrial respiration, were assayed in real time for a panel of wild-type (wt) and mutant (mut) TP53 SCCHN cell lines in an extracellular flux analyser (XF24, Seahorse Bioscience, Billerica, MA, USA) during specifically designed stress tests. Sensitivity to radiation with or without 25mM 2-deoxyglucose (glycolytic inhibitor) was evaluated in clonogenic assays. FindingsMutTP53 SCCHN cell lines showed a distinct metabolic phenotype from that of wtTP53 cells: wtTP53 cells maintained metabolic diversity, displaying robust mitochondrial and glycolytic reserve capacities, whereas mutTP53 cells displayed glycolytic dependence with markedly reduced mitochondrial and glycolytic reserve, functioning near capacity under basal conditions. This metabolic shift, in turn, correlated with radiation response after administration of 2-deoxyglucose, which significantly (p<0·05) potentiated effects of radiation in mutTP53 but not wtTP53 cells. InterpretationTP53 mutation in SCCHN seems to correlate with a metabolic shift away from mitochondrial respiration towards glycolysis, resulting in sensitivity to the potentiating effects of glycolytic inhibition on radiation. Consequently, TP53 status could be applied clinically as a marker of metabolic phenotype in SCCHN, enabling a more tailored therapeutic approach, which would also specifically target the typically treatment-resistant disease associated with TP53 mutation. FundingCancer Research UK, Royal College of Surgeons of England.