A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The MET oncogenic pathway drives aggressive cancers resistant to chemotherapy.
• Current therapies struggle to specifically target the MET pathway.
• Anticalins offer a novel approach for developing precise cancer pathway antagonists.

Purpose of the Study:

• To evaluate PRS-110, a novel monovalent anticalin, as a MET antagonist.
• To assess PRS-110's efficacy in both ligand-dependent and ligand-independent cancer models.
• To investigate PRS-110's mechanism of action on MET signaling and cellular localization.

Main Methods:

• Characterization of PRS-110 binding affinity and inhibition of HGF interaction with MET.
• Phosphorylation assays to assess MET signaling inhibition and agonistic activity.
• Confocal microscopy to observe MET receptor trafficking.
• In vivo xenograft studies in mice using U87-MG and Caki-1 cancer models.

Main Results:

• PRS-110 demonstrated high-affinity binding to MET, blocking HGF interaction and inhibiting MET phosphorylation.
• The antagonist PRS-110 induced MET trafficking to late endosomal/lysosomal compartments.
• Significant, dose-dependent tumor growth inhibition was observed in both ligand-dependent and ligand-independent xenograft models.
• Reduced total MET levels in xenograft tumors confirmed PRS-110's ligand-independent mechanism.

Conclusions:

• PRS-110 is a potent, specific monovalent MET antagonist with demonstrated in vitro and in vivo anticancer activity.
• The drug exhibits efficacy in both ligand-dependent and ligand-independent cancer models, suggesting broad applicability.
• PRS-110 warrants further clinical investigation for patients with aggressive, difficult-to-treat MET-driven cancers.