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Cancer Therapy: Preclinical

Dasatinib (BMS-354825) Tyrosine Kinase Inhibitor Suppresses Invasion and Induces Cell Cycle Arrest and Apoptosis of Head and Neck Squamous Cell Carcinoma and Non–Small Cell Lung Cancer Cells

Faye M. Johnson, Babita Saigal, Moshe Talpaz and Nicholas J. Donato
Faye M. Johnson
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Babita Saigal
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Moshe Talpaz
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Nicholas J. Donato
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DOI: 10.1158/1078-0432.CCR-05-0757 Published October 2005
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Abstract

Purpose: Epithelial tumors, including non–small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), present clinical challenges. One potential target for systemic therapy is Src family nonreceptor tyrosine kinases, which are overexpressed in these tumors and induce pleiotropic effects, including increased proliferation, enhanced survival, stimulation of angiogenesis, and changes in motility. Dasatinib (BMS-354825), an ATP-competitive, small molecule tyrosine kinase inhibitor, suppresses the activity of these kinases at subnanomolar concentrations. Therefore, we tested the antitumor effects of this inhibitor in vitro to determine whether in vivo analyses were warranted.

Experimental Design: The antitumor effects of dasatinib on HNSCC and NSCLC cells were evaluated using assays to measure cell cycle progression, apoptosis, migration, and invasion. Western blotting was used to monitor its effects on cell signaling.

Results: Dasatinib inhibited migration and invasion in all cell lines and induced cell cycle arrest (blocking the G1-S transition) and apoptosis in some lines. The effects on migration and invasion correlated with the inhibition of Src and downstream mediators of adhesion [e.g., focal adhesion kinase (FAK), p130, and paxillin], and the cell cycle effects and apoptosis correlated with the induction of p27 and the dephosphorylation of Rb. Dasatinib also induced morphologic changes that were consistent with an upstream role for Src in regulating focal adhesion complexes.

Conclusions: This study showed that Src inhibition in HNSCC and NSCLC has antitumor effects in vitro. This suggests that dasatinib would have therapeutic activity against these tumors. Clinical studies in these tumor types are warranted.

  • Src
  • BMS-354825
  • dasatinib
  • tyrosine kinase inhibitor
  • head and neck squamous cell carcinoma
  • non–small cell lung cancer

Footnotes

  • ↵4 Unpublished data.

  • Grant support: Physician Scientist Award from M.D. Anderson Cancer Center (F.M. Johnson) and grant PO1 CA46939 (N.J. Donato).

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted July 7, 2005.
    • Received April 5, 2005.
    • Revision received June 6, 2005.
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Clinical Cancer Research: 11 (19)
October 2005
Volume 11, Issue 19
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Dasatinib (BMS-354825) Tyrosine Kinase Inhibitor Suppresses Invasion and Induces Cell Cycle Arrest and Apoptosis of Head and Neck Squamous Cell Carcinoma and Non–Small Cell Lung Cancer Cells
Faye M. Johnson, Babita Saigal, Moshe Talpaz and Nicholas J. Donato
Clin Cancer Res October 1 2005 (11) (19) 6924-6932; DOI: 10.1158/1078-0432.CCR-05-0757

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Dasatinib (BMS-354825) Tyrosine Kinase Inhibitor Suppresses Invasion and Induces Cell Cycle Arrest and Apoptosis of Head and Neck Squamous Cell Carcinoma and Non–Small Cell Lung Cancer Cells
Faye M. Johnson, Babita Saigal, Moshe Talpaz and Nicholas J. Donato
Clin Cancer Res October 1 2005 (11) (19) 6924-6932; DOI: 10.1158/1078-0432.CCR-05-0757
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Clinical Cancer Research
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