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Title: Off-target effects of c-MET inhibitors on thyroid cancer cells
Authors: Zhou, Y.
Zhao, C.
Gery, S.
Braunstein, G.D.
Okamoto, R.
Alvarez, R.
Miles, S.A.
Doan, N.B.
Said, J.W.
Gu, J.
Phillip Koeffler, H. 
Issue Date: Jan-2013
Citation: Zhou, Y., Zhao, C., Gery, S., Braunstein, G.D., Okamoto, R., Alvarez, R., Miles, S.A., Doan, N.B., Said, J.W., Gu, J., Phillip Koeffler, H. (2013-01). Off-target effects of c-MET inhibitors on thyroid cancer cells. Molecular Cancer Therapeutics 13 (1) : 134-143. ScholarBank@NUS Repository.
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. © 2013 American Association for Cancer Research.
Source Title: Molecular Cancer Therapeutics
ISSN: 15357163
DOI: 10.1158/1535-7163.MCT-13-0187
Appears in Collections:Staff Publications

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