MET Tyrosine Kinase Inhibitor Crizotinib (PF-02341066) Shows Differential Antitumor Effects in Non-small Cell Lung Cancer According to MET Alterations

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MET Tyrosine Kinase Inhibitor Crizotinib (PF-02341066) Shows Differential Antitumor Effects in Non-small Cell Lung Cancer According to MET Alterations Junko Tanizaki, MD, Isamu Okamoto, MD, PhD, Kunio Okamoto, MD, PhD, Ken Takezawa, MD, PhD, Kiyoko Kuwata, PhD, Haruka Yamaguchi, PhD, Kazuhiko Nakagawa, MD, PhD Journal of Thoracic Oncology Volume 6, Issue 10, Pages 1624-1631 (October 2011) DOI: 10.1097/JTO.0b013e31822591e9 Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Effects of crizotinib on MET, AKT, and extracellular signal-regulated kinase (ERK) phosphorylation and on apoptosis in lung cancer cell lines. A, The indicated cell lines were incubated with or without crizotinib (100 nM) for 24 hours, after which cell lysates were prepared and subjected to immunoblot analysis with antibodies to phosphorylated (p) or total forms of MET, AKT, or ERK or to β-actin (loading control). B, Cells were incubated for 72 hours with or without crizotinib (100 nM), after which the number of apoptotic cells was determined by staining with annexin V and propidium iodide followed by flow cytometry. Data are means ± SE from three independent experiments. C, Cells incubated as in (B) were lysed and subjected to immunoblot analysis with antibodies to poly(ADP-ribose) polymerase (PARP) or to β-actin. Journal of Thoracic Oncology 2011 6, 1624-1631DOI: (10.1097/JTO.0b013e31822591e9) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Effects of depletion of MET on signal transduction and apoptosis in lung cancer cells. A, The indicated cell lines were transfected with nonspecific (control) or MET small interfering RNAs (siRNAs) for 48 hours, after which cell lysates were prepared and subjected to immunoblot analysis with antibodies to phosphorylated (p) or total forms of MET, AKT, or ERK or to β-actin. B, Cells were transfected with nonspecific (control) or MET siRNAs for 72 hours, after which the number of apoptotic cells was determined by staining with annexin V and propidium iodide followed by flow cytometry. Data are means ± SE from three independent experiments. C, Cells transfected as in B were lysed and subjected to immunoblot analysis with antibodies to poly(ADP-ribose) polymerase (PARP) or to β-actin. Journal of Thoracic Oncology 2011 6, 1624-1631DOI: (10.1097/JTO.0b013e31822591e9) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Effects of BIM depletion and forced expression of survivin on apoptosis induced by crizotinib in lung cancer cells with MET amplification. A, EBC-1 and H1993 cells were incubated with or without crizotinib (100 nM) for 48 hours, after which cell lysates were prepared and subjected to immunoblot analysis with antibodies to the indicated proteins. The position of the band corresponding to BIMEL is indicated. B, Cells were transfected with BIM or nonspecific small interfering RNAs (siRNAs) for 24 hours and then incubated for 72 hours with or without crizotinib (100 nM). The cells were then lysed and subjected to immunoblot analysis with antibodies to the indicated proteins (left panel), or they were evaluated for apoptosis by staining with annexin V and propidium iodide followed by flow cytometry (right panel). C, Cells were transfected with an expression vector for survivin or with the corresponding empty vector (Mock) for 24 hours, incubated with or without 100 nM crizotinib for 72 hours, and then analyzed as in (B). Quantitative data in (B) and (C) are means ± SE from three independent experiments. *p < 0.05 for the indicated comparisons. Journal of Thoracic Oncology 2011 6, 1624-1631DOI: (10.1097/JTO.0b013e31822591e9) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Effect of crizotinib on the growth of lung cancer cells in vivo. Nude mice with tumor xenografts established by subcutaneous injection of EBC-1 (A), H1437 (B), or A549 (C) cells were treated daily for 4 weeks with vehicle (control) or crizotinib (25 or 50 mg/kg). Tumor volume was determined at the indicated times after the onset of treatment. Data are means ± SE for 5 mice/group. *p < 0.05 for crizotinib (25 or 50 mg/kg) at 28 days versus the corresponding control value. Journal of Thoracic Oncology 2011 6, 1624-1631DOI: (10.1097/JTO.0b013e31822591e9) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions