Apatinib modulates sorafenib-resistant hepatocellular carcinoma through inhibiting the EGFR/JNK/ERK signaling pathway

Oncol Res. 2025 May 29;33(6):1459-1472. doi: 10.32604/or.2025.060407. eCollection 2025.

Abstract

Objectives: Apatinib has been reported to be a promising treatment for sorafenib-resistant hepatocellular carcinoma (HCC) patients. However, the underlying mechanism remains ambiguous. The study aimed to explore the efficacy of apatinib in sorafenib-resistant HCC and the underlying mechanism both in vitro and in vivo.

Methods: After observing epithelial-mesenchymal transformation (EMT) changes in HepG2 and HepG2/Sorafenib cells, we treated them with varying concentrations of apatinib to assess its impact on sorafenib-resistant HCC. Subsequently, specific inhibitors of c-Jun N-terminal kinase (JNK, SP600125) and extracellular signal-regulated kinase (ERK, PD98059) were introduced to investigate whether apatinib influenced sorafenib-resistant HCC via modulation of the epidermal growth factor receptor (EGFR)/JNK/ERK signaling pathway in vitro and in vivo. Biological behavior changes were assessed through cell counting kit-8 (CCK-8), colony formation, transwell, and immunofluorescence tests. Simultaneously, Western blot analysis was conducted to elucidate the expression of proteins associated with EMT and the EGFR/JNK/ERK signaling pathway.

Results: The HepG2/Sorafenib cells exhibited greater resistance to sorafenib compared to HepG2 cells, and sorafenib-resistant HCC was characterized by EMT changes. Apatinib demonstrated concentration-dependent inhibition of biological behaviors in HepG2/Sorafenib cells, with minimal impact on HepG2 cells. Additionally, apatinib had a pronounced effect on the expression of EMT-related proteins in sorafenib-resistant cells similar to that in sorafenib-sensitive cells. Furthermore, there was a dose-dependent reduction in the expression of proteins associated with the EGFR/JNK/ERK pathway in apatinib-treated groups. Notably, SP600125 and PD98059 contributed to the inhibition of EMT and EGFR/JNK/ERK pathway-related proteins by apatinib in sorafenib-resistant HCC.

Conclusion: Apatinib potentially hindered the progression of sorafenib-resistant HCC by suppressing both EMT and the EGFR/JNK/ERK pathway.

Keywords: Apatinib; EGFR/JNK/ERK; Epithelial mesenchymal transformation; Hepatocellular carcinoma (HCC); Sorafenib resistance.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Hepatocellular* / drug therapy
  • Carcinoma, Hepatocellular* / metabolism
  • Carcinoma, Hepatocellular* / pathology
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm* / drug effects
  • Epithelial-Mesenchymal Transition / drug effects
  • ErbB Receptors / metabolism
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / pathology
  • MAP Kinase Signaling System* / drug effects
  • Mice
  • Protein Kinase Inhibitors / pharmacology
  • Pyridines* / pharmacology
  • Signal Transduction / drug effects
  • Sorafenib* / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Sorafenib
  • apatinib
  • Pyridines
  • ErbB Receptors
  • EGFR protein, human
  • Antineoplastic Agents
  • Protein Kinase Inhibitors