MDM2-NFAT1 dual inhibitor, MA242: Effective against hepatocellular carcinoma, independent of p53. (10th September 2019)

• Record Type: Journal Article
• Authors: Wang, Wei; Cheng, Jian-Wen; Qin, Jiang-Jiang; Hu, Bo; Li, Xin; Nijampatnam, Bhavitavya; Velu, Sadanandan E.; Fan, Jia; Yang, Xin-Rong; Zhang, Ruiwen
• Is Part Of: Cancer letters. Volume 459(2019)
• Page Start: 156
• Page End: 167
• Publication Date: 2019-09-10
• Subjects: Hepatocellular carcinoma -- MDM2 -- NFAT1 -- Metastasis -- CRISPR/Cas9 -- Patient-derived xenograft; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.114429
• Languages: English
• ISSNs: 0304-3835

Abstract

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. Highlights: High tumor expression of MDM2 and NFAT1 predicts a poor prognosis in HCC patients. Targeting both MDM2 and NFAT1 represents a novel strategy for the treatment of HCC. MA242 directly binds to both the MDM2 and NFAT1 proteins with high affinity and induces their protein degradation. MA242 could be safely and effectively used to treat orthotopic and PDX HCC tumors, independent of the p53 status.