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: Emanuela Pupo, Nadia Ducano, Barbara Lupo, Elisa Vigna, Daniele Avanzato, Timothy Perera, Livio Trusolino, Letizia Lanzetti, Paolo M Comoglio
• Journal: Cancer research (Cancer Res) Vol. 76 Issue 17 Pg. 5019-29 (09 01 2016) ISSN: 1538-7445 [Electronic] United States
• PMID: 27364553 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Antibodies
• Antineoplastic Agents
• Protein Kinase Inhibitors
• MET protein, human
• Proto-Oncogene Proteins c-met

Topics

• Animals
• Antibodies (pharmacology)
• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Female
• Fluorescent Antibody Technique
• Humans
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Microscopy, Confocal
• Neoplasm Recurrence, Local (metabolism, pathology)
• Neoplasms, Experimental (metabolism, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-met (metabolism)
• Xenograft Model Antitumor Assays