Individualizing antimetabolic treatment strategies for head and neck squamous cell carcinoma based on TP53 mutational status

Abstract

Mutations in the tumor protein 53 (TP53) tumor suppressor gene are common in head and neck squamous cell carcinoma (HNSCC) and correlate with radioresistance. Currently, there are no clinically available therapeutic approaches targeting p53 in HNSCC. In this report, the authors propose a strategy that uses TP53 mutational status to individualize antimetabolic strategies for the potentiation of radiation toxicity in HNSCC cells. Glycolytic flux and mitochondrial respiration were evaluated in wild-type (wt) and mutant (mut) TP53 HNSCC cell lines. Sensitivity to external-beam radiation (XRT) was measured using a clonogenic assay. HNSCC cells that expressed mutTP53 demonstrated radioresistance compared with HNSCC cells that expressed wtTP53. Glycolytic inhibition potentiated radiation toxicity in mutTP53-expressing, but not wtTP53-expressing, HNSCC cells. The relative sensitivity of mutTP53 HNSCC cells to glycolytic inhibition was caused by a glycolytic dependence associated with decreased mitochondrial complex II and IV activity. The wtTP53-expressing cells maintained mitochondrial reserves and were relatively insensitive to glycolytic inhibition. Inhibition of respiration using metformin increased glycolytic dependence in wtTP53-expressing cells and potentiated the effects of glycolyic inhibition on radiation toxicity. TP53 mutation in HNSCC cells was correlated with a metabolic shift away from mitochondrial respiration toward glycolysis, resulting in increased sensitivity to the potentiating effects of glycolytic inhibition on radiation toxicity. In contrast, wtTP53-expressing cells required inhibition of both mitochondrial respiration and glycolysis to become sensitized to radiation. Therefore, the authors concluded that TP53 mutational status may be used as a marker of altered tumor cell metabolism to individualize HNSCC treatment selection of specific, targeted metabolic agents that can overcome cellular resistance to radiation therapy.