Inhibition of the MET Kinase Activity and Cell Growth in MET-Addicted Cancer Cells by Bi-Paratopic Linking |
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| Institution: | 1. Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland;2. Department of Molecular Medicine, University of Pavia, Italy;3. Department of Chemistry, Bielefeld University, Germany;1. Dipartimento di Scienze Biomediche Sperimentali e Cliniche “Mario Serio”- Università degli Studi di Firenze, Viale Morgagni 50, 50134, Firenze, Italy;2. Dipartimento di Medicina Sperimentale e Clinica - Università degli Studi di Firenze, Largo Brambilla 3, 50134, Firenze, Italy;3. Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca, Piazza della Scienza 2, 20126, Milano, Italy;4. Dipartimento di Fisica G. Occhialini, Università degli Studi di Milano-Bicocca, Piazza della Scienza 3, 20126, Milano, Italy;5. Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus University College London, NW3 2PF, London, UK;6. Dipartimento di Medicina Molecolare, Istituto di Biochimica, Università degli Studi di Pavia, 27100, Pavia, Italy;7. Centro Interuniversitario per lo Studio delle Malattie Neurodegenerative (CIMN), 50134, Firenze, Italy;1. LBPA, UMR 8113, ENS Paris-Saclay—CNRS, 61 avenue du Président Wilson, 94235 Cachan cedex, France;2. LPTM, CNRS UMR 8089, Université de Cergy-Pontoise, 2 avenue Adolphe Chauvin, 95031 Cergy-Pontoise, France;1. Dipartimento di Medicina Molecolare, Unità di Immunologia e Patologia generale, Università degli Studi di Pavia, Pavia, Italy;2. Istituto di Genetica Molecolare (IGM) del CNR, Pavia, Italy |
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| Abstract: | MET, the product of the c-MET proto-oncogene, and its ligand hepatocyte growth factor/scatter factor (HGF/SF) control survival, proliferation and migration during development and tissue regeneration. HGF/SF-MET signaling is equally crucial for growth and metastasis of a variety of human tumors, but resistance to small-molecule inhibitors of MET kinase develops rapidly and therapeutic antibody targeting remains challenging. We made use of the designed ankyrin repeat protein (DARPin) technology to develop an alternative approach for inhibiting MET. We generated a collection of MET-binding DARPins covering epitopes in the extracellular MET domains and created comprehensive sets of bi-paratopic fusion proteins. This new class of molecules efficiently inhibited MET kinase activity and downstream signaling, caused receptor downregulation and strongly inhibited the proliferation of MET-dependent gastric carcinoma cells carrying MET locus amplifications. MET-specific bi-paratopic DARPins may represent a novel and potent strategy for therapeutic targeting of MET and other receptors, and this study has elucidated their mode of action. |
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