GSK3 alpha and beta are new functionally relevant targets of tivantinib in lung cancer cells.
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's anticancer properties are unrelated to c-MET inhibition. Consistently, in determining tivantinib's 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 GSK3α than for GSK3β and that pharmacological inhibition or simultaneous siRNA-mediated loss of GSK3α and GSK3β caused apoptosis. In summary, GSK3α and GSK3β are new kinase targets of tivantinib that play an important role in its cellular mechanism-of-action in NSCLC.
Department of Drug Discovery, ‡Department of Thoracic Oncology, and §Molecular Oncology and Proteomics, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida 33612-9497, United States.
Lily L
LL
Remsing Rix
Brent M
BM
Kuenzi
Yunting
Y
Luo
Elizabeth
E
Remily-Wood
Fumi
F
Kinose
Gabriela
G
Wright
Jiannong
J
Li
John M
JM
Koomen
Eric B
EB
Haura
Harshani R
HR
Lawrence
Uwe
U
Rix
D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D058990:Molecular Targeted Therapy; D011760:Pyrrolidinones / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*
C551661:ARQ 197; D011760:Pyrrolidinones; D011804:Quinolines; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha