Four individually druggable MET hotspots mediate HGF-driven tumor progression

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Hepatocyte growth factor (HGF) binding to its receptor MET is crucial for tumor growth and spread.
• Understanding the precise interaction sites is key to developing targeted cancer therapies.

Purpose of the Study:

• To identify novel binding sites on MET for HGF.
• To develop and characterize antibodies that block HGF-MET interactions.
• To evaluate the therapeutic potential of these antibodies in preclinical cancer models.

Main Methods:

• Utilized a llama platform for generating human-like antibodies.
• Selected antibodies that compete with HGF for MET binding.
• Characterized antibody binding sites on MET domains using biochemical and biological assays.
• Tested antibody efficacy in glioblastoma, triple-negative breast cancer, and colorectal cancer models.

Main Results:

• Identified four distinct HGF-binding hotspots on MET, including novel regions.
• Developed antibodies targeting these hotspots that effectively inhibit HGF/MET signaling.
• Demonstrated that selected antibodies reduce brain invasion, prevent metastasis, and suppress cancer cell dissemination in vivo.

Conclusions:

• Multiple regions of MET are involved in HGF-mediated tumor progression.
• The HGF-MET interaction is more complex than previously understood.
• Targeting these identified MET regions with novel antibodies offers a promising strategy for cancer therapy.