{
  "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.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "name": "Limu Lou"
    },
    {
      "name": "Haokang Feng"
    },
    {
      "name": "Xinxin Zhang"
    },
    {
      "name": "Heng Wang"
    },
    {
      "name": "Yunhao Fan"
    },
    {
      "name": "Yibao Tao"
    },
    {
      "name": "Zefan Zhang"
    },
    {
      "name": "Chao-Po Lin"
    },
    {
      "name": "Yunfan Sun"
    },
    {
      "name": "Liye Zhang",
      "orcid": "0000-0003-2104-6828"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cmy4m5vgsnr1w.bib",
  "cited_by": 0,
  "doi": "10.1016/j.celrep.2026.118196",
  "fulltext_url": "http://www.sciencedirect.com/science/article/pii/S2211124726012751",
  "id": "cmy4m5vgsnr1w",
  "issns": [
    "2211-1247"
  ],
  "landing_url": "https://doi.org/10.1016/j.celrep.2026.118196",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "http://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "QH301-705.5"
    ],
    [
      "openalex",
      "2721|Hepatocellular Carcinoma Treatment and Prognosis"
    ]
  ],
  "openalex": "W7223186824",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-30",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/cmy4m5vgsnr1w.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:25Z",
      "native_id": "13dd5304ad164acda7239d207b3b0399",
      "source": "doaj",
      "url": "https://doi.org/10.1016/j.celrep.2026.118196"
    },
    {
      "first_seen": "2026-10-30T12:19:34Z",
      "native_id": "10.1016/j.celrep.2026.118196",
      "source": "crossref",
      "url": "https://linkinghub.elsevier.com/retrieve/pii/S2211124726012751"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2721|Hepatocellular Carcinoma Treatment and Prognosis",
      "subfield": "general"
    }
  ],
  "title": "AREG mediates transient hepatocellular carcinoma resistance to receptor tyrosine kinase inhibitors",
  "title_text": "AREG mediates transient hepatocellular carcinoma resistance to receptor tyrosine kinase inhibitors",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:43:39Z",
  "url": "https://research.draconitic.com/paper/cmy4m5vgsnr1w",
  "venue": "Cell Reports",
  "versions": []
}