AREG mediates transient hepatocellular carcinoma resistance to receptor tyrosine kinase inhibitors
Abstract
Lenvatinib is a first-line therapy for hepatocellular carcinoma (HCC), yet resistance remains a major clinical challenge. Emerging studies suggest resistance evolves through dynamic multi-step processes. Here, using multi-timepoint and multi-omics sampling, we characterized the trajectory of lenvatinib resistance in HCC cells and identified three adaptive states marked by state transitions. Multi-omics analyses and functional validation identified amphiregulin (AREG) as a key transient mediator of resistance in our models. AREG is a sufficient and dominant ligand to promote cell survival through epidermal growth factor receptor (EGFR) activation. Pharmacological inhibition of the AREG-EGFR axis specifically targeted early-resistant cells. Furthermore, AREG upregulation was validated in additional replicate experiments and another HCC cell line. Mechanistically, a focal deletion on chromosome 3p may contribute to NF-κB activation and AREG expression. This study delineates a recurrent yet transient adaptive mechanism and suggests new therapeutic opportunities—such as combination therapies targeting transient resistance mechanisms—to prevent or overcome drug resistance.
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BibTeX
@article{lou2026areg,
title = {{AREG mediates transient hepatocellular carcinoma resistance to receptor tyrosine kinase inhibitors}},
author = {Limu Lou and Haokang Feng and Xinxin Zhang and Heng Wang and Yunhao Fan and Yibao Tao and Zefan Zhang and Chao-Po Lin and Yunfan Sun and Liye Zhang},
journal = {Cell Reports},
year = {2026},
month = oct,
doi = {10.1016/j.celrep.2026.118196},
url = {https://doi.org/10.1016/j.celrep.2026.118196},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - AREG mediates transient hepatocellular carcinoma resistance to receptor tyrosine kinase inhibitors
AU - Limu Lou
AU - Haokang Feng
AU - Xinxin Zhang
AU - Heng Wang
AU - Yunhao Fan
AU - Yibao Tao
AU - Zefan Zhang
AU - Chao-Po Lin
AU - Yunfan Sun
AU - Liye Zhang
PY - 2026
DA - 2026/10/30
JO - Cell Reports
DO - 10.1016/j.celrep.2026.118196
UR - https://doi.org/10.1016/j.celrep.2026.118196
AB - Lenvatinib is a first-line therapy for hepatocellular carcinoma (HCC), yet resistance remains a major clinical challenge. Emerging studies suggest resistance evolves through dynamic multi-step processes. Here, using multi-timepoint and multi-omics sampling, we characterized the trajectory of lenvatinib resistance in HCC cells and identified three adaptive states marked by state transitions. Multi-omics analyses and functional validation identified amphiregulin (AREG) as a key transient mediator of resistance in our models. AREG is a sufficient and dominant ligand to promote cell survival through epidermal growth factor receptor (EGFR) activation. Pharmacological inhibition of the AREG-EGFR axis specifically targeted early-resistant cells. Furthermore, AREG upregulation was validated in additional replicate experiments and another HCC cell line. Mechanistically, a focal deletion on chromosome 3p may contribute to NF-κB activation and AREG expression. This study delineates a recurrent yet transient adaptive mechanism and suggests new therapeutic opportunities—such as combination therapies targeting transient resistance mechanisms—to prevent or overcome drug resistance.
SN - 2211-1247
ER -