title: Rebound Effects Caused by Withdrawal of MET Kinase Inhibitor Are Quenched by a MET Therapeutic Antibody.
abstract: MET oncogene amplification is emerging as a major mechanism of acquired resistance to EGFR-directed therapy in lung and colorectal cancers. Furthermore, MET amplification predicts responsiveness to MET inhibitors currently in clinical trials. Among the anti-MET drugs available, ATP-competitive small-molecule kinase inhibitors abrogate receptor autophosphorylation and downstream activation of ERK1/2 and AKT, resulting in cell-cycle arrest. However, this antiproliferative effect allows persistence of a pool of cancer cells that are quiescent but alive. Once the inhibition is removed, rebound activation of MET-driven cell proliferative pathways and tumor growth may occur, an adverse event observed frequently in clinical settings after drug discontinuation. Here we show that inhibitor withdrawal prompts receptor phosphorylation to levels higher than those displayed at steady-state and generates a rebound effect pushing quiescent cancer cells back into the cell cycle, both in vitro and in experimental tumor models in vivo Mechanistically, we found that inhibitor treatment blocks MET endocytosis, causing a local increase in the number of receptors at the plasma membrane. Upon inhibitor washout, the receptor is readily rephosphorylated. The initial phosphorylation is not only increased but also prolonged in duration due to downmodulation of a phosphatase-mediated MET-negative feedback loop, which accompanies receptor internalization. Notably, treatment with a MET therapeutic antibody that induces proteolytic cleavage of the receptor at the cell surface substantially prevents this rebound effect, providing a rationale to combine or alternate these mechanistically different types of MET-targeted therapy. Cancer Res; 76(17); 5019-29. ©2016 AACR.
authors.affiliation: Membrane Trafficking, IRCCS, Candiolo, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pupo
authors.affiliation: Membrane Trafficking, IRCCS, Candiolo, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Ducano
authors.affiliation: Translational Cancer Medicine, IRCCS, Candiolo, Italy. Department of Oncology, University of Torino Medical School, Torino, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Lupo
authors.affiliation: Gene Transfer and Therapy, IRCCS, Candiolo, Italy. Department of Oncology, University of Torino Medical School, Torino, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Vigna
authors.affiliation: Membrane Trafficking, IRCCS, Candiolo, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Avanzato
authors.affiliation: Octimet Oncology Ltd, Oxfordshire, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Perera
authors.affiliation: Translational Cancer Medicine, IRCCS, Candiolo, Italy. Department of Oncology, University of Torino Medical School, Torino, Italy.
authors.forename: Livio
authors.initials: L
authors.lastname: Trusolino
authors.affiliation: Membrane Trafficking, IRCCS, Candiolo, Italy. Department of Oncology, University of Torino Medical School, Torino, Italy. letizia.lanzetti@ircc.it paolo.comoglio@ircc.it.
authors.forename: Letizia
authors.initials: L
authors.lastname: Lanzetti
authors.affiliation: Molecular Therapeutics and Exploratory Research Laboratories at Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy. Department of Oncology, University of Torino Medical School, Torino, Italy. letizia.lanzetti@ircc.it paolo.comoglio@ircc.it.
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology*; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met