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Updated: Oct 25, 2025
Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
Published on: September 19, 2018
Systems analysis identifies endothelin 1 axis blockade for enhancing the anti-tumor effect of multikinase inhibitor
Chae Young Hwang1,2, Su Jong Yu3, Jae-Kyung Won1,4
1Laboratory for Systems Biology and Bio-inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
Abstract:
Multikinase inhibitors, such as sorafenib, are used for the treatment of advanced carcinomas but the response shows limited efficacy or varies a lot with patients. Here we adopted the systems approach combined with high-throughput data analysis to discover key mechanism embedded in the drug response. When analyzing the transcriptomic data from the Cancer Cell Line Encyclopedia (CCLE) database, endothelin 1 (EDN1) was enriched in cancer cells with low responsiveness to sorafenib. We found that the level of EDN1 is higher in the tissue and blood of hepatocellular carcinoma (HCC) patients showing poor response to sorafenib. In vitro experiment showed that EDN1 not only induces activation of angiogenic-promoting pathways in HCC cells but also stimulates proliferation and migration. Moreover, EDN1 is related with poor responsiveness to sorafenib by mitigating unfolded protein response (UPR), which was validated in both transcriptomic data analysis and in silico simulation. Finally, we found that endothelin receptor B (EDNRB) antagonists can enhance the efficacy of sorafenib in both HCC cells and xenograft mouse models. Our findings provide that EDN1 is a novel diagnostic marker for sorafenib responsiveness in HCC and a basis for testing macitentan, which is currently used for pulmonary artery hypertension, in combination with sorafenib in advanced HCC patients.
Insights
Endothelin 1 (EDN1) is linked to poor sorafenib response in liver cancer. Targeting EDN1 or its receptor may improve treatment efficacy for advanced hepatocellular carcinoma (HCC).
Area of Science:
- Oncology
- Molecular Biology
- Systems Biology
Background:
- Sorafenib, a multikinase inhibitor, shows variable efficacy in advanced carcinomas.
- Identifying mechanisms of drug response is crucial for personalized cancer therapy.
Purpose of the Study:
- To uncover key mechanisms underlying sorafenib response in cancer using a systems approach.
- To identify biomarkers and therapeutic targets for improving sorafenib efficacy in hepatocellular carcinoma (HCC).
Main Methods:
- Analysis of transcriptomic data from the Cancer Cell Line Encyclopedia (CCLE) database.
- In vitro experiments assessing the role of endothelin 1 (EDN1) in HCC cells.
- In silico simulation and validation using transcriptomic data.
- Evaluation of endothelin receptor B (EDNRB) antagonists in HCC models.
Main Results:
- Endothelin 1 (EDN1) was enriched in sorafenib-resistant cancer cells and elevated in HCC patients with poor sorafenib response.
- EDN1 promotes angiogenesis, proliferation, and migration in HCC cells.
- EDN1 mitigates the unfolded protein response (UPR), contributing to sorafenib resistance.
- EDNRB antagonists enhanced sorafenib efficacy in HCC cells and mouse models.
Conclusions:
- EDN1 serves as a potential diagnostic marker for sorafenib responsiveness in HCC.
- Targeting the EDN1/EDNRB pathway offers a novel therapeutic strategy for advanced HCC.
- Combination therapy with sorafenib and EDNRB antagonists warrants clinical investigation.
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