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

## TL;DR

Apatinib may help treat sorafenib-resistant liver cancer by blocking a key signaling pathway and reducing cancer cell spread.

## Contribution

Apatinib's mechanism in overcoming sorafenib resistance in hepatocellular carcinoma is revealed through EGFR/JNK/ERK pathway inhibition.

## Key findings

- Apatinib inhibited biological behaviors in sorafenib-resistant HepG2 cells in a concentration-dependent manner.
- Apatinib reduced EMT-related proteins and EGFR/JNK/ERK pathway activity in resistant cells.
- JNK and ERK inhibitors enhanced apatinib's effect on EMT and pathway suppression.

## Abstract

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.

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.

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.

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