Liver X Receptor Agonism Sensitizes a Subset of Hepatocellular Carcinoma to Sorafenib by Dual-Inhibiting MET and EGFR

Neoplasia. 2020 Jan;22(1):1-9. doi: 10.1016/j.neo.2019.08.002. Epub 2019 Nov 18.

Abstract

Sorafenib is the first approved systemic therapy for advanced hepatocellular carcinoma (HCC) and is the first-line choice in clinic. Sustained activation of receptor tyrosine kinases (RTKs) is associated with low efficacy of sorafenib in HCC. Activation of liver X receptor (LXR) has been reported to inhibit some RTKs. In this study, we found that the LXR agonist enhanced the anti-tumor activity of sorafenib in a subset of HCC cells with high LXR-β/α gene expression ratio. Mechanically, the activation of LXR suppressed sorafenib dependent recruitment of MET and epidermal growth factor receptor (EGFR) in lipid rafts through cholesterol efflux. Our findings imply that LXR agonist can serve as a potential sensitizer to enhance the anti-tumor effect of sorafenib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / etiology
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cholesterol / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • ErbB Receptors / antagonists & inhibitors
  • Humans
  • Immunohistochemistry
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / etiology
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Liver X Receptors / agonists*
  • Male
  • Mice
  • Protein Binding
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Sorafenib / pharmacology*
  • Sorafenib / therapeutic use
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Liver X Receptors
  • Protein Kinase Inhibitors
  • Cholesterol
  • Sorafenib
  • EGFR protein, human
  • ErbB Receptors
  • MET protein, human
  • Proto-Oncogene Proteins c-met