MDM2-NFAT1 dual inhibitor, MA242: Effective against hepatocellular carcinoma, independent of p53

Cancer Lett. 2019 Sep 10:459:156-167. doi: 10.1016/j.canlet.2019.114429. Epub 2019 Jun 7.

Abstract

The overexpression of the MDM2 oncoprotein frequently occurs in hepatocellular carcinoma (HCC). Small molecules that inhibit MDM2-p53 binding show efficacy against p53 wild-type HCC, but most patients have p53-mutant tumors and intrinsic resistance to such MDM2 inhibitors. We have recently discovered that the NFAT1 transcription factor upregulates MDM2 expression, but the role of NFAT1 in HCC is not fully understood. The present study was designed to develop a dual-targeting (MDM2 and NFAT1) strategy for the treatment of HCC. We herein demonstrate that high expression levels of NFAT1 and MDM2 are independent predictors of a poor prognosis in patients with HCC. We have also identified a MDM2 and NFAT1 dual inhibitor (termed MA242) that induces MDM2 auto-ubiquitination and degradation and represses NFAT1-mediated MDM2 transcription. MA242 profoundly inhibits the growth and metastasis of HCC cells in vitro and in vivo, independent of p53. The present efficacy and mechanistic studies provide proof-of-principle data to support the therapeutic value of this dual targeting strategy in future drug discovery.

Keywords: CRISPR/Cas9; Hepatocellular carcinoma; MDM2; Metastasis; NFAT1; Patient-derived xenograft.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Movement
  • Female
  • Hep G2 Cells
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Middle Aged
  • Models, Molecular
  • NFATC Transcription Factors / antagonists & inhibitors*
  • NFATC Transcription Factors / biosynthesis
  • NFATC Transcription Factors / metabolism
  • Neoplasm Invasiveness
  • Prognosis
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / biosynthesis
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Signal Transduction / drug effects
  • Tumor Suppressor Protein p53
  • Ubiquitination
  • Xenograft Model Antitumor Assays

Substances

  • Heterocyclic Compounds, 3-Ring
  • MA242
  • NFATC Transcription Factors
  • NFATC2 protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2