2. Academic Validation
  3. Molecular Dissection of the AHR-AREG driven EGFR-ERK1/2-CyclinD1 axis in acquired lenvatinib resistance of Hepatocellular carcinoma

Molecular Dissection of the AHR-AREG driven EGFR-ERK1/2-CyclinD1 axis in acquired lenvatinib resistance of Hepatocellular carcinoma

  • Biochem Pharmacol. 2025 Sep:239:117032. doi: 10.1016/j.bcp.2025.117032.
Yuelei Hu 1,  Ruilin Wang 2,  Jinmei Diao 3,  Lin An 4,  Juan Liu 5,  Dawei Sun 6
Affiliations

Affiliations

  • 1 Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China.
  • 2 Department of Cadre's Wards Ultrasound Diagnostics. Ultrasound Diagnostic Center, The First Hospital of Jilin University, Jilin University, Changchun, China.
  • 3 Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.
  • 4 Department of Dermatology, China-Japan Union Hospital of Jilin University, No.126 Xiantai Street, Changchun 130033, China. Electronic address: anlin2022@jlu.edu.cn.
  • 5 Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China. Electronic address: lja02720@btch.edu.cn.
  • 6 Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China. Electronic address: sundawei2008@jlu.edu.cn.
PMID: 40482839 DOI: 10.1016/j.bcp.2025.117032
Abstract

Lenvatinib serves as a first-line systemic therapy for advanced hepatocellular carcinoma (HCC), yet the development of resistance poses a major clinical challenge. The purpose of this study is to investigate the mechanisms underlying lenvatinib resistance in HCC and identify potential interventions. We established lenvatinib-resistant HuH7 and Hep3B cell lines and conducted in vitro, bioinformatics, and biochemical assays to explore and validate the mechanisms underlying acquired resistance to lenvatinib in HCC. Additionally, cellular xenograft models of lenvatinib-resistant HCC were utilized to assess tumor responses to a novel drug treatment regimen. Our findings revealed a shift from suppression to activation in the expression of p-ERK1/2 and Cyclin D1 in HCC cells as they transitioned from sensitivity to resistance to lenvatinib. Furthermore, we demonstrated that targeting ERK1/2 with ravoxertinib (an ERK1/2 inhibitor) could significantly enhance the sensitivity of resistant HCC cells to lenvatinib therapy. Through transcriptome data analysis and experimental validation, we identified Amphiregulin (AREG), induced autocrinely by lenvatinib, as a critical mediator that activates the EGFR-ERK1/2 signaling pathway, leading to increased Cyclin D1 expression in HCC cells. Mechanistically, lenvatinib promotes Aryl Hydrocarbon Receptor (AHR) nuclear translocation, directly activating AREG transcription. Using in vivo models, we further confirmed that inhibiting ERK1/2 with ravoxertinib or AHR with CH-223191 (an AHR inhibitor) could overcome lenvatinib resistance in HCC. Overall, lenvatinib-induced AHR activation promotes AREG expression, which subsequently facilitates the acquisition of drug resistance in HCC via the EGFR-ERK1/2-CyclinD1 signaling axis. Targeting ERK1/2 and AHR effectively improved the response to lenvatinib treatment in resistant HCC.

Keywords

Amphiregulin; Aryl Hydrocarbon Receptor; Hepatocellular Carcinoma; Lenvatinib.

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