CASE REPORT article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1659463
HGF and NF1 mutations as putative bypass mechanisms of MET inhibitor resistance in hepatocellular carcinoma: A case study
Provisionally accepted
- 1Shulan Hangzhou Hospital, Hangzhou, China
- 2The Third People's Hospital of Zhengzhou, Zhengzhou, China
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Background: Hepatocellular carcinoma (HCC) is a highly aggressive liver cancer with poor prognosis, often associated with resistance to treatment. MET amplification has been identified as a potential therapeutic target, but resistance to MET inhibitors, such as crizotinib, remains a significant challenge. This study aims to explore the molecular mechanisms underlying resistance to MET inhibitors in MET-amplified HCC. Methods: We present a case of advanced HCC in a patient with MET amplification treated with crizotinib. After initial tumor regression, disease progression occurred. Genetic analysis using next-generation sequencing (NGS) was performed on biopsy samples taken before and after progression to identify mutations associated with resistance. Results: NGS revealed the loss of MET amplification and identified HGF and NF1 mutations as potential bypass mechanisms. Specifically, a missense mutation in HGF (p.G401A) was observed, which may enhance ligand-receptor binding, while an NF1 mutation (p.M546L) may permit sustained MAPK and PI3K activation despite MET inhibition. These observations are preliminary and require validation in larger patient cohorts. Conclusion: Our findings suggest that acquired resistance to MET inhibitors in MET-amplified HCC may involve clonal evolution and activation of compensatory signaling pathways. These insights highlight the need for dynamic molecular surveillance and the development of strategies targeting multiple pathways to overcome resistance and improve patient outcomes. Keywords: Hepatocellular carcinoma, MET amplification, Crizotinib resistance, Molecular resistance mechanisms, HGF and NF1 mutations.
Keywords: Hepatocellular Carcinoma, MET amplification, Crizotinib resistance, molecular resistance mechanisms, HGF and NF1 mutations
Received: 04 Jul 2025; Accepted: 15 Oct 2025.
Copyright: © 2025 Chen, Luo, Gu and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Qiyong Li, liqiyong@zju.edu.cn
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