title: Off-target effects of c-MET inhibitors on thyroid cancer cells.
abstract: Aberrantly activated c-MET signaling occurs in several cancers, promoting the development of c-MET inhibitors. In this study, we found that eight of eight thyroid cancer cell lines (including six anaplastic thyroid cell lines) have prominent expression of c-MET protein. Fifty percent of the thyroid cancer cell lines (four of eight) were growth inhibited by two small molecule c-MET inhibitors (tivantinib and crizotinib) associated with apoptosis and G(2)-M cell-cycle arrest. However, crizotinib did not inhibit 50% proliferation of thyroid cancer cells (SW1736 and TL3) at a concentration at which the drug completely inhibited ligand-stimulated c-MET phosphorylation. However, tivantinib was less potent than crizotinib at inhibiting c-MET phosphorylation, but was more potent than crizotinib at decreasing cell growth. Suppressing c-MET protein expression and phosphorylation using siRNA targeting c-MET did not induce cell-cycle arrest and apoptosis. Taken together, tivantinib and crizotinib have off-target(s) activity, contributing to their antitumor activity. In vivo study showed that crizotinib markedly inhibited the growth of thyroid cancer cells (SW1736) in immunodeficient mice. In summary, c-MET inhibitors (tivantinib and crizotinib) suppress the growth of aggressive thyroid cancer cells, and this potential therapeutic benefit results from their non-MET-targeting effects.
authors.affiliation: Corresponding Authors: Yan Zhou, Department of Pathology, School of Basic Medical Sciences, Peking (Beijing) University, Beijing, China. zzz2008yyy@gmail.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Conghui
authors.initials: C
authors.lastname: Zhao
authors.forename: Sigal
authors.initials: S
authors.lastname: Gery
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Braunstein
authors.forename: Ryoko
authors.initials: R
authors.lastname: Okamoto
authors.forename: Rocio
authors.initials: R
authors.lastname: Alvarez
authors.forename: Steven A
authors.initials: SA
authors.lastname: Miles
authors.forename: Ngan B
authors.initials: NB
authors.lastname: Doan
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Said
authors.forename: Jiang
authors.initials: J
authors.lastname: Gu
authors.forename: H
authors.initials: H
authors.lastname: Phillip Koeffler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics; D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D011760:Pyrrolidinones / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C551661:ARQ 197; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011760:Pyrrolidinones; D011804:Quinolines; D000077547:Crizotinib; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met