A receptor-antibody hybrid hampering MET-driven metastatic spread

Chiara Modica,Cristina Basilico,Elisa Vigna,Paolo M Comoglio,Cristina Chiriaco,Nicla Borrelli

doi:10.1186/s13046-020-01822-5

Abstract

BackgroundThe receptor encoded by the MET oncogene and its ligand Hepatocyte Growth Factor (HGF) are at the core of the invasive-metastatic behavior. In a number of instances genetic alterations result in ligand-independent onset of malignancy (MET addiction). More frequently, ligand stimulation of wild-type MET contributes to progression toward metastasis (MET expedience). Thus, while MET inhibitors alone are effective in the first case, combination therapy with ligand inhibitors is required in the second condition.MethodsIn this paper, we generated hybrid molecules gathering HGF and MET inhibitory properties. This has been achieved by ‘head-to-tail’ or ‘tail-to-head’ fusion of a single chain Fab derived from the DN30 MET antibody with a recombinant ‘ad-hoc’ engineered MET extracellular domain (decoyMET), encompassing the HGF binding site but lacking the DN30 epitope.ResultsThe hybrid molecules correctly bind MET and HGF, inhibit HGF-induced MET downstream signaling, and quench HGF-driven biological responses, such as growth, motility and invasion, in cancer cells of different origin. Two metastatic models were generated in mice knocked-in by the human HGF gene: (i) orthotopic transplantation of pancreatic cancer cells; (ii) subcutaneous injection of primary cells derived from a cancer of unknown primary. Treatment with hybrid molecules strongly affects time of onset, number, and size of metastatic lesions.ConclusionThese results provide a strategy to treat metastatic dissemination driven by the HGF/MET axis.

Highlights

The receptor encoded by the MET oncogene and its ligand Hepatocyte Growth Factor (HGF) are at the core of the invasive-metastatic behavior
We previously demonstrated that concomitant targeting of HGF and MET has therapeutic efficacy in counteracting MET expedience [17]
We engineer a fusion protein assembling in a single agent the inhibitory properties toward the ligand and the receptor, providing a novel tool to fight metastatic spread driven by MET expedience

Summary

Introduction

The receptor encoded by the MET oncogene and its ligand Hepatocyte Growth Factor (HGF) are at the core of the invasive-metastatic behavior. The MET oncogene encodes for a tyrosine kinase, the high affinity receptor of hepatocyte growth factor (HGF). The HGF/MET axis drives a complex biological program known as ‘invasive growth’ including cell-cell dissociation (scattering), extracellular matrix degradation, dissemination at distant sites, cell proliferation, and survival [1]. These processes, pivotal during embryonal development, tissue homeostasis, and wound healing, are aberrantly harnessed by cancer cells during tumor progression [2, 3]. We engineer a fusion protein assembling in a single agent the inhibitory properties toward the ligand and the receptor, providing a novel tool to fight metastatic spread driven by MET expedience

Methods

Results

Conclusion