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|Title:||Off-target effects of c-MET inhibitors on thyroid cancer cells||Authors:||Zhou, Y.
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. https://doi.org/10.1158/1535-7163.MCT-13-0187||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||URI:||http://scholarbank.nus.edu.sg/handle/10635/125424||ISSN:||15357163||DOI:||10.1158/1535-7163.MCT-13-0187|
|Appears in Collections:||Staff Publications|
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