Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer

Cells. 2021 Jul 6;10(7):1715. doi: 10.3390/cells10071715.

Abstract

Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.

Keywords: ICIs; TKIs; drug resistance; hypoxia; liver cancer; metabolic reprogramming; metabolism.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cellular Reprogramming / drug effects*
  • Cellular Reprogramming / genetics
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hypoxia / drug therapy*
  • Hypoxia / genetics
  • Hypoxia / metabolism
  • Hypoxia / pathology
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Immune Checkpoint Inhibitors / therapeutic use
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Metabolic Networks and Pathways / drug effects
  • Metabolic Networks and Pathways / genetics
  • Nivolumab / therapeutic use
  • Protein Kinase Inhibitors / therapeutic use
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / genetics
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / metabolism
  • Sorafenib / therapeutic use
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / genetics

Substances

  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immune Checkpoint Inhibitors
  • PDK1 protein, human
  • Protein Kinase Inhibitors
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Nivolumab
  • Sorafenib
  • pembrolizumab