Targeting EphA2 suppresses hepatocellular carcinoma initiation and progression by dual inhibition of JAK1/STAT3 and AKT signaling

Cell Rep. 2021 Feb 23;34(8):108765. doi: 10.1016/j.celrep.2021.108765.

Abstract

Hepatocellular carcinoma (HCC) remains one of the deadliest malignancies worldwide. One major obstacle to treatment is a lack of effective molecular-targeted therapies. In this study, we find that EphA2 expression and signaling are enriched in human HCC and associated with poor prognosis. Loss of EphA2 suppresses the initiation and growth of HCC both in vitro and in vivo. Furthermore, CRISPR/CAS9-mediated EphA2 inhibition significantly delays tumor development in a genetically engineered murine model of HCC. Mechanistically, we discover that targeting EphA2 suppresses both AKT and JAK1/STAT3 signaling, two separate oncogenic pathways in HCC. We also identify a small molecule kinase inhibitor of EphA2 that suppresses tumor progression in a murine HCC model. Together, our results suggest EphA2 as a promising therapeutic target for HCC.

Keywords: AKT; EphA2; HCC; JAK1; STAT3.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Benzamides / pharmacology*
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Databases, Genetic
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Janus Kinase 1 / genetics
  • Janus Kinase 1 / metabolism*
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptor, EphA2 / antagonists & inhibitors*
  • Receptor, EphA2 / genetics
  • Receptor, EphA2 / metabolism
  • Retrospective Studies
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • ALW-II-41-27
  • Antineoplastic Agents
  • Benzamides
  • EPHA2 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • Niacinamide
  • Receptor, EphA2
  • JAK1 protein, human
  • Jak1 protein, mouse
  • Janus Kinase 1
  • Proto-Oncogene Proteins c-akt