By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the few cancers with a continuous increase in incidence and mortality. Drug resistance is a major problem in the treatment of HCC. In this study, two sorafenib‐resistant HCC cell lines and a nude mouse subcutaneously tumor model were used to explore the possible mechanisms leading to sorafenib resistance, and to investigate whether aspirin could increase the sensitivity of hepatoma cells to sorafenib. The combination of aspirin and sorafenib resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo. High glycolysis and PFKFB3 overexpression occupied a dominant position in sorafenib resistance, and can be targeted and overcome by aspirin. Aspirin plus sorafenib induced apoptosis in tumors without inducing weight loss, hepatotoxicity or inflammation. Our results suggest that aspirin overcomes sorafenib resistance and their combination may be an effective treatment approach for HCC. What's new? Sorafenib, a kinase inhibitor, is one of the most effective drugs available for the treatment of hepatocellular carcinoma (HCC). Its use, however, is limited by acquired resistance. The present study shows that the expression of PFKFB3, a gene involved in glycolytic flux that encodes 6‐phosphofructo‐1‐kinase 2 (PFK2), is strongly associated with sorafenib resistance in HCC cells. PFK is a suspected target of aspirin, a drug associated with reduced HCC risk. Experiments in cells and animals reveal the existence of a synergistic antitumor effect between aspirin and sorafenib, suggesting that sorafenib‐resistant HCC patients may benefit from combined treatment with aspirin.