American Association for Cancer Research
15357163mct110934-sup-fig2.pdf (137.38 kB)

Supplementary Figure 2 from Antitumor Action of the MET Tyrosine Kinase Inhibitor Crizotinib (PF-02341066) in Gastric Cancer Positive for MET Amplification

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journal contribution
posted on 2023-04-03, 13:42 authored by Wataru Okamoto, Isamu Okamoto, Tokuzo Arao, Kiyoko Kuwata, Erina Hatashita, Haruka Yamaguchi, Kazuko Sakai, Kazuyoshi Yanagihara, Kazuto Nishio, Kazuhiko Nakagawa

PDF file, 138KB, Effects of crizotinib on cell cycle distribution in gastric cancer cells with MET amplification.



Therapeutic strategies that target the tyrosine kinase MET hold promise for gastric cancer, but the mechanism underlying the antitumor activity of such strategies remains unclear. We examined the antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer cells positive or negative for MET amplification. Inhibition of MET signaling by crizotinib or RNA interference–mediated MET depletion resulted in induction of apoptosis accompanied by inhibition of AKT and extracellular signal–regulated kinase phosphorylation in gastric cancer cells with MET amplification but not in those without it, suggesting that MET signaling is essential for the survival of MET amplification–positive cells. Crizotinib upregulated the expression of BIM, a proapoptotic member of the Bcl-2 family, as well as downregulated that of survivin, X-linked inhibitor of apoptosis protein (XIAP), and c-IAP1, members of the inhibitor of apoptosis protein family, in cells with MET amplification. Forced depletion of BIM inhibited crizotinib-induced apoptosis, suggesting that upregulation of BIM contributes to the proapoptotic effect of crizotinib. Crizotinib also exhibited a marked antitumor effect in gastric cancer xenografts positive for MET amplification, whereas it had little effect on those negative for this genetic change. Crizotinib thus shows a marked antitumor action both in vitro and in vivo specifically in gastric cancer cells positive for MET amplification. Mol Cancer Ther; 11(7); 1557–64. ©2012 AACR.

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