Related Experiment Video

Updated: Jun 23, 2025

An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis

Published on: September 12, 2019

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HDAC Inhibition Sensitize Hepatocellular Carcinoma to Lenvatinib via Suppressing AKT Activation

Shuai Yan1, Lu Chen2, Hao Zhuang3

  • 1Translational Cancer Research Center, Peking University First Hospital, Beijing 100034, China.

International Journal of Biological Sciences
|June 21, 2024
PubMed

Insights

This study identifies SAHA as a potential treatment for Lenvatinib-resistant hepatocellular carcinoma (HCC). Combining Lenvatinib with SAHA or an AKT inhibitor reverses resistance and inhibits cancer growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Hepatocellular carcinoma (HCC) is a significant global health concern with limited therapeutic options for advanced stages.
  • Lenvatinib is a first-line treatment for advanced HCC, but drug resistance significantly curtails its clinical efficacy.
  • Understanding Lenvatinib resistance mechanisms is crucial for developing effective HCC treatment strategies.

Purpose of the Study:

  • To identify novel therapeutic strategies to overcome Lenvatinib resistance in hepatocellular carcinoma.
  • To investigate the potential of HDAC inhibitors, specifically SAHA, in combination therapy for HCC.
  • To elucidate the molecular mechanisms underlying SAHA's efficacy in reversing Lenvatinib resistance.

Main Methods:

  • Screening of a customized drug library to identify compounds active against Lenvatinib-resistant HCC.
  • Mechanism of action studies involving SAHA, including analysis of PTEN and AKT signaling pathways.
  • In vitro and in vivo validation of combination therapies using Lenvatinib with SAHA or an AKT inhibitor (AZD5363) in HCC cell lines and patient-derived organoids.

Main Results:

  • SAHA demonstrated significant anti-tumor activity against Lenvatinib-resistant HCC organoids.
  • SAHA was found to upregulate PTEN expression and suppress AKT signaling, thereby reversing Lenvatinib resistance.
  • Combination therapy of Lenvatinib with SAHA or AZD5363 exhibited synergistic effects, inhibiting HCC cell proliferation and inducing apoptosis.

Conclusions:

  • SAHA is a promising agent for overcoming Lenvatinib resistance in HCC by modulating the PTEN/AKT pathway.
  • Combination therapies involving Lenvatinib with HDAC inhibitors (like SAHA) or AKT inhibitors show potential for enhanced HCC treatment.
  • These findings support the development of novel combination strategies to improve outcomes for patients with advanced HCC.
Keywords:
AKTHepatocellular carcinomaLenvatinib resistanceSAHAcombination treatment

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