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 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.
Highlights
Gastric cancer is the second most frequent cause of cancer deaths worldwide [1]
Rabbit polyclonal antibodies to phosphorylated human MET, total AKT, phosphorylated AKT, phosphorylated extracellular signal–regulated kinase (ERK), total STAT3, phosphorylated STAT3, PARP, caspase-3, BIM, Bcl-2, and X-linked inhibitor of apoptosis protein (XIAP) were obtained from Cell Signaling Technology; those to total ERK were from Santa Cruz Biotechnology; those to total MET were from Zymed/Invitrogen; those to survivin were from Novus; those to c-IAP1 were from R&D
To identify the signaling pathways responsible for upregulation or downregulation of apoptosis-related proteins by crizotinib, we examined the effects of specific inhibitors of the mitogen-activated protein (MAP)/ERK kinase (MEK) and of phosphoinositide 3-kinase (PI3K) in MET amplification–positive cell lines
Summary
Gastric cancer is the second most frequent cause of cancer deaths worldwide [1]. Chemotherapy has a beneficial effect on survival in individuals with advancedstage gastric cancer, but even so overall survival is usually still only about 1 year [1, 2]. Substantial advances in the development of molecularly targeted therapies for gastric cancer have been achieved in recent years [3]. Amplification of the proto-oncogene MET is a frequent molecular abnormality in gastric cancer [4,5,6], and a MET-tyrosine kinase inhibitor (TKI) has been shown to induce apoptosis in gastric cancer cells with MET amplification [7, 8]. Crizotinib (PF-02341066; Fig. 1A) was recently approved by the U.S Food and Drug Administration.
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