Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification

Wataru Okamoto, Isamu Okamoto, Tokuzo Arao, Kiyoko Kuwata, Erina Hatashita, Haruka Yamaguchi, Kazuko Sakai, Kazuyoshi Yanagihara, Kazuto Nishio, Kazuhiko Nakagawa

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish
Pages (from-to)1557-1564
Number of pages8
JournalMolecular Cancer Therapeutics
Volume11
Issue number7
DOIs
Publication statusPublished - Jul 1 2012
Externally publishedYes

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Protein-Tyrosine Kinases
Stomach Neoplasms
X-Linked Inhibitor of Apoptosis Protein
Apoptosis
Inhibitor of Apoptosis Proteins
crizotinib
Extracellular Signal-Regulated MAP Kinases
RNA Interference
Heterografts
Up-Regulation
Down-Regulation
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification. / Okamoto, Wataru; Okamoto, Isamu; Arao, Tokuzo; Kuwata, Kiyoko; Hatashita, Erina; Yamaguchi, Haruka; Sakai, Kazuko; Yanagihara, Kazuyoshi; Nishio, Kazuto; Nakagawa, Kazuhiko.

In: Molecular Cancer Therapeutics, Vol. 11, No. 7, 01.07.2012, p. 1557-1564.

Research output: Contribution to journalArticle

Okamoto, W, Okamoto, I, Arao, T, Kuwata, K, Hatashita, E, Yamaguchi, H, Sakai, K, Yanagihara, K, Nishio, K & Nakagawa, K 2012, 'Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification', Molecular Cancer Therapeutics, vol. 11, no. 7, pp. 1557-1564. https://doi.org/10.1158/1535-7163.MCT-11-0934
Okamoto, Wataru ; Okamoto, Isamu ; Arao, Tokuzo ; Kuwata, Kiyoko ; Hatashita, Erina ; Yamaguchi, Haruka ; Sakai, Kazuko ; Yanagihara, Kazuyoshi ; Nishio, Kazuto ; Nakagawa, Kazuhiko. / Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification. In: Molecular Cancer Therapeutics. 2012 ; Vol. 11, No. 7. pp. 1557-1564.
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