ANTITUMOR ACTION OF THE MET TYROSINE KINASE INHIBITOR CRIZOTINIB (PF-02341066) IN GASTRIC CANCER POSITIVE FOR MET AMPLIFICATION

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Abstract

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 ERK 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 up-regulated the expression of BIM, a proapoptotic member of the Bcl-2 family, as well as down-regulated that of survivin, 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 up-regulation 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.

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