Mechanism and strategies of hypoxia-inducible factor-mediated resistance to tyrosine kinase inhibitors in hepatocellular carcinoma
The use of tyrosine kinase inhibitors(TKI)has been an important advance in the systemic treatment of hepatocellular carcinoma,but their sustained anti-angiogenic therapy leads to increased tumor hypoxia,accelerates the development of a hypoxic microenvironment and promotes the expressions of hypoxia-inducible factors(HIF),thereby inducing drug resistance of tumor patients to TKI.This paper summarizes the mechanism of action of HIF mediating TKI resistance in hepatocellular carcinoma in aspects of metabolic reprogramming,abnormal expressions of cancer and cancer-associated genes,and ferroptosis,and sorts resistance response strategies to provide reference for clinical solutions to TKI resistance issues.As results show,HIF/glycolysis axis inhibitors(isoflavonoid genistein,simvastatin,etc.)can improve TKI resistance based on metabolic reprogramming mechanism;oncogene-targeted inhibitors combined with TKI(the combination of capsaicin and sorafenib)can improve TKI resistance based on abnormal expression of cancer and cancer-related genes;fatty acid synthase inhibitor(orlistat)can improve TKI resistance based on ferroptosis mechanism.
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