GSK3 Alpha and Beta Are New Functionally Relevant Targets of Tivantinib in Lung Cancer Cells
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- 作者：Lily L. Remsing Rix ; Brent M. Kuenzi ; Yunting Luo ; Elizabeth Remily-Wood ; Fumi Kinose ; Gabriela Wright ; Jiannong Li ; John M. Koomen ; Eric B. Haura ; Harshani R. Lawrence ; Uwe Rix
- 刊名：ACS Chemical Biology
- 出版年：2014
- 出版时间：February 21, 2014
- 年：2014
- 卷：9
- 期：2
- 页码：353-358
- 全文大小：382K
- ISSN：1554-8937
文摘
Tivantinib has been described as a potent and highly selective inhibitor of the receptor tyrosine kinase c-MET and is currently in advanced clinical development for several cancers including non-small cell lung cancer (NSCLC). However, recent studies suggest that tivantinib鈥檚 anticancer properties are unrelated to c-MET inhibition. Consistently, in determining tivantinib鈥檚 activity profile in a broad panel of NSCLC cell lines, we found that, in contrast to several more potent c-MET inhibitors, tivantinib reduces cell viability across most of these cell lines. Applying an unbiased, mass-spectrometry-based, chemical proteomics approach, we identified glycogen synthase kinase 3 (GSK3) alpha and beta as novel tivantinib targets. Subsequent validation showed that tivantinib displayed higher potency for GSK3伪 than for GSK3尾 and that pharmacological inhibition or simultaneous siRNA-mediated loss of GSK3伪 and GSK3尾 caused apoptosis. In summary, GSK3伪 and GSK3尾 are new kinase targets of tivantinib that play an important role in its cellular mechanism-of-action in NSCLC.