BCRP/ABCG2 inhibition sensitizes hepatocellular carcinoma cells to sorafenib
Wei-Chien Huang1, Yi-Ling Hsieh2, Chao-Ming Hung3
1Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan ; Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan ; The Ph.D. program for Cancer Biology and Drug Discovery, China Medical University, Taichung, Taiwan ; Department of Biotechnology, Asia University, Taichung, Taiwan.
Abstract:
The multikinase inhibitor, sorafenib (Nexavar®, BAY43-9006), which inhibits both the Raf/MEK/ERK pathway and several receptor tyrosine kinases (RTKs), has shown significantly therapeutic benefits in advanced hepatocellular carcinoma (HCC). However, not all HCC patients respond to sorafenib well and new therapeutic strategies to optimize the efficacy of sorafenib are urgently required. Overexpression of breast cancer resistance protein (BCRP/ABCG2) mediates the drug-efflux of several tyrosine kinase inhibitors (TKIs) to attenuate their efficacy. This study aimed to investigate the role of BCRP/ABCG2 in the sensitivity of HCC to sorafenib. Our data showed that BCRP/ABCG2 mediated the efflux of sorafenib. Co-treatment with a BCRP/ABCG2 inhibitor greatly augmented the cytotoxicity of sorafenib in HCC cells. Similar results were also achieved by the competitive inhibitor of BCRP/ABCG2, gefitinib, in combination with sorafenib. These results suggest not only that BCRP/ABCG2 is a potential predictor for the sorafenib sensitivity in HCC, but also that blockage of BCRP/ABCG2 may be a potential strategy to increase the response of HCC cells to sorafenib.
Insights
Breast cancer resistance protein (BCRP/ABCG2) affects sorafenib efficacy in liver cancer. Inhibiting BCRP/ABCG2 enhances sorafenib
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Sorafenib is a multikinase inhibitor beneficial for advanced hepatocellular carcinoma (HCC).
- Not all HCC patients respond effectively to sorafenib, necessitating improved therapeutic strategies.
- Breast cancer resistance protein (BCRP/ABCG2) overexpression can reduce tyrosine kinase inhibitor (TKI) efficacy through drug efflux.
Purpose of the Study:
- To investigate the role of BCRP/ABCG2 in determining hepatocellular carcinoma (HCC) sensitivity to sorafenib.
- To explore BCRP/ABCG2 as a potential therapeutic target for enhancing sorafenib treatment in HCC.
Main Methods:
- Investigated the mechanism of sorafenib efflux mediated by BCRP/ABCG2 in HCC cells.
- Evaluated the effect of co-treating HCC cells with sorafenib and a BCRP/ABCG2 inhibitor.
- Assessed the impact of gefitinib, a competitive BCRP/ABCG2 inhibitor, in combination with sorafenib.
Main Results:
- BCRP/ABCG2 was confirmed to mediate the efflux of sorafenib.
- Co-administration of a BCRP/ABCG2 inhibitor significantly increased sorafenib's cytotoxicity in HCC cells.
- Gefitinib combined with sorafenib also demonstrated enhanced anti-cancer effects in HCC cells.
Conclusions:
- BCRP/ABCG2 acts as a mediator of sorafenib drug efflux in hepatocellular carcinoma.
- BCRP/ABCG2 may serve as a predictive biomarker for sorafenib response in HCC patients.
- Blocking BCRP/ABCG2 represents a promising strategy to improve sorafenib efficacy in HCC treatment.
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