MET tyrosine kinase inhibitor crizotinib (PF-02341066) shows differential antitumor effects in non-small cell lung cancer according to MET alterations

Junko Tanizaki, Isamu Okamoto, Kunio Okamoto, Ken Takezawa, Kiyoko Kuwata, Haruka Yamaguchi, Kazuhiko Nakagawa

Research output: Contribution to journalArticle

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Abstract

Introduction: Tyrosine kinase inhibitors (TKIs) targeted to MET are undergoing clinical trials in patients with solid tumors, but the precise mechanism of the antitumor activity of these drugs remains unclear. We examined the antitumor action of the MET-TKI crizotinib (PF-02341066) in lung cancer cells that are positive or negative for MET amplification or mutation. Methods: The antitumor action of crizotinib was evaluated on the basis of signal transduction, cell proliferation, apoptosis, and progression of tumor xenografts. Results: Inhibition of MET signaling by crizotinib or by RNA interference-mediated MET depletion resulted in the induction of apoptosis accompanied by inhibition of AKT and extracellular signal-regulated kinase phosphorylation in lung cancer cells with MET amplification but not in cells with a MET mutation or in those without amplification or mutation of MET. These results suggest that MET signaling is essential for the survival of cells with MET amplification but not for that of cells without this genetic change, including those with a MET mutation. Crizotinib up-regulated the expression of BIM, a proapoptotic member of the Bcl-2 family, and down-regulated that of survivin, a member of the inhibitor of apoptosis protein family, in cells with MET amplification. Forced depletion of BIM and expression of survivin each inhibited crizotinib-induced apoptosis, suggesting that both up-regulation of BIM and down-regulation of survivin contribute to the proapoptotic effect of crizotinib. Conclusions: Crizotinib shows a marked antitumor action in MET amplification-positive lung cancer cells but not in cells without MET amplification, including those with a MET mutation.

Original languageEnglish
Pages (from-to)1624-1631
Number of pages8
JournalJournal of Thoracic Oncology
Volume6
Issue number10
DOIs
Publication statusPublished - Jan 1 2011
Externally publishedYes

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Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Mutation
Lung Neoplasms
Apoptosis
Inhibitor of Apoptosis Proteins
crizotinib
Extracellular Signal-Regulated MAP Kinases
RNA Interference
Heterografts
Antineoplastic Agents
Signal Transduction
Neoplasms
Cell Survival
Up-Regulation
Down-Regulation
Phosphorylation
Cell Proliferation
Clinical Trials

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

MET tyrosine kinase inhibitor crizotinib (PF-02341066) shows differential antitumor effects in non-small cell lung cancer according to MET alterations. / Tanizaki, Junko; Okamoto, Isamu; Okamoto, Kunio; Takezawa, Ken; Kuwata, Kiyoko; Yamaguchi, Haruka; Nakagawa, Kazuhiko.

In: Journal of Thoracic Oncology, Vol. 6, No. 10, 01.01.2011, p. 1624-1631.

Research output: Contribution to journalArticle

Tanizaki, Junko ; Okamoto, Isamu ; Okamoto, Kunio ; Takezawa, Ken ; Kuwata, Kiyoko ; Yamaguchi, Haruka ; Nakagawa, Kazuhiko. / MET tyrosine kinase inhibitor crizotinib (PF-02341066) shows differential antitumor effects in non-small cell lung cancer according to MET alterations. In: Journal of Thoracic Oncology. 2011 ; Vol. 6, No. 10. pp. 1624-1631.
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