Related Experiment Video
Updated: Apr 4, 2026
Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
Published on: September 30, 2019
Targeting FGFR Pathway in Human Hepatocellular Carcinoma: Expressing pFGFR and pMET for Antitumor Activity
Jae-Cheol Jo1, Eun Kyoung Choi2, Jae-Sik Shin2
1Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.
Abstract:
The MET receptor tyrosine kinase, the receptor for hepatocyte growth factor (HGF), has been implicated in cancer growth, invasion, migration, angiogenesis, and metastasis in a broad variety of human cancers, including human hepatocellular carcinoma (HCC). Recently, MET was suggested to be a potential target for the personalized treatment of HCC with an active HGF-MET signaling pathway. However, the mechanisms of resistance to MET inhibitors need to be elucidated to provide effective treatment. Here, we show that HCC cells exhibit different sensitivities to the MET inhibitor PHA665752, depending on the phosphorylation status of FGFR. Treatment of cells expressing both phospho-FGFR and phospho-MET with the inhibitor PHA665752 did not cause growth inhibition and cell death, whereas treatment with AZD4547, a pan-FGFR inhibitor, resulted in decreased colony formation and cleavage of caspase-3. Moreover, silencing of endogenous FGFR1 and FGFR2 by RNAi of HCC cells expressing phospho-FGFR, phospho-FGFR2, and phospho-MET overcame the resistance to PHA665752 treatment. Treatment of primary cancer cells from patients with HCC expressing both phospho-FGFR and phospho-MET with PHA665752 did not induce cell death, whereas AZD4547 treatment induced cell death through the cleavage of caspase-3. In addition, treatment of cells resistant to PHA665752 with AZD4547 abrogated the activation of downstream effectors of cell growth, proliferation, and survival. On the basis of these results, we conclude that the FGFR pathway is critical for HCC survival, and that targeting this pathway with AZD4547 may be beneficial for the treatment of patients with HCC-expressing phospho-FGFR and phospho-MET.
Insights
Hepatocellular carcinoma (HCC) cells resistant to MET inhibitors can be treated with FGFR inhibitors. Targeting the FGFR pathway with AZD4547 shows promise for treating HCC patients with specific molecular markers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The MET receptor tyrosine kinase is crucial for hepatocellular carcinoma (HCC) progression.
- MET inhibitors are potential personalized treatments for HCC, but resistance mechanisms require elucidation.
- FGFR signaling may play a role in HCC cell survival and resistance to MET inhibition.
Purpose of the Study:
- To investigate the mechanisms of resistance to MET inhibitors in HCC.
- To explore the role of FGFR signaling in HCC cell survival and MET inhibitor resistance.
- To evaluate the efficacy of FGFR inhibition in overcoming MET inhibitor resistance in HCC.
Main Methods:
- Assessing HCC cell sensitivity to MET inhibitor PHA665752 based on FGFR phosphorylation status.
- Treating HCC cells with PHA665752 and pan-FGFR inhibitor AZD4547.
- Silencing FGFR1 and FGFR2 using RNA interference (RNAi) in HCC cells.
- Analyzing effects on cell growth, colony formation, and apoptosis (caspase-3 cleavage).
- Evaluating treatment responses in primary HCC patient-derived cells.
Main Results:
- HCC cells with both phospho-FGFR and phospho-MET showed resistance to PHA665752.
- AZD4547 treatment inhibited colony formation and induced apoptosis in resistant HCC cells.
- Silencing FGFR1/FGFR2 in HCC cells restored sensitivity to PHA665752.
- AZD4547 induced cell death in primary HCC cells resistant to PHA665752.
- AZD4547 abrogated downstream signaling pathways involved in HCC cell growth and survival.
Conclusions:
- The FGFR pathway is critical for HCC cell survival, particularly in the context of MET signaling.
- FGFR inhibition, using AZD4547, can overcome resistance to MET inhibitors in HCC.
- Targeting the FGFR pathway with AZD4547 may offer a therapeutic strategy for HCC patients with specific molecular profiles (phospho-FGFR and phospho-MET).
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:38Mitogens and the Cell Cycle
01:24Liver Regeneration
Cells of Liver
The liver comprises four major types of cells— hepatocytes, stellate, Kupffer, and sinusoidal endothelial cells. The hepatocytes are...