# Case Report: HGF and NF1 mutations as putative bypass mechanisms of MET inhibitor resistance in hepatocellular carcinoma: a case study

## TL;DR

This case study explores how HCC tumors develop resistance to MET inhibitors by identifying HGF and NF1 mutations as possible bypass mechanisms.

## Contribution

The study identifies HGF and NF1 mutations as novel potential resistance mechanisms to MET inhibitors in MET-amplified hepatocellular carcinoma.

## Key findings

- Loss of MET amplification and emergence of HGF and NF1 mutations were observed after disease progression.
- HGF p.G401A and NF1 p.M546L mutations may enable sustained signaling despite MET inhibition.
- The findings suggest resistance involves clonal evolution and compensatory pathways.

## Abstract

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.

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.

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.

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.