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Molecular Predictors of Sensitivity to the MET Inhibitor PHA665752 in Lung Carcinoma Cells  Daisuke Matsubara, MD, PhD, Shumpei Ishikawa, MD, PhD, Sachiko.

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Presentation on theme: "Molecular Predictors of Sensitivity to the MET Inhibitor PHA665752 in Lung Carcinoma Cells  Daisuke Matsubara, MD, PhD, Shumpei Ishikawa, MD, PhD, Sachiko."— Presentation transcript:

1 Molecular Predictors of Sensitivity to the MET Inhibitor PHA665752 in Lung Carcinoma Cells 
Daisuke Matsubara, MD, PhD, Shumpei Ishikawa, MD, PhD, Sachiko Oguni, Hiroyuki Aburatani, MD, PhD, Masashi Fukayama, MD, PhD, Toshiro Niki, MD, PhD  Journal of Thoracic Oncology  Volume 5, Issue 9, Pages (September 2010) DOI: /JTO.0b013e3181e2a409 Copyright © 2010 International Association for the Study of Lung Cancer Terms and Conditions

2 FIGURE 1 Sensitivity of 41 non-small cell lung cancer cell lines to PHA and their genetic statuses. Left panel shows cell line names, histologies, sources, sensitivities, and the values of IC50. Middle panel shows the viability of cells with each PHA concentration in a different color. Right panel shows the genetic statuses of 41 cell lines. Details are shown at the bottom of the figure. L27 was described in a previous study.11 Journal of Thoracic Oncology 2010 5, DOI: ( /JTO.0b013e3181e2a409) Copyright © 2010 International Association for the Study of Lung Cancer Terms and Conditions

3 FIGURE 2 Dose-response curves of representative cell lines of each group: H1648 (sensitive), PC14 (intermediate), and LC-2/ad (resistant). The x axis indicates the log10(concentration of PHA665752) and the y axis indicates the %cell viability = (mean absorbance in test wells)/(mean absorbance in control well) × 100. Journal of Thoracic Oncology 2010 5, DOI: ( /JTO.0b013e3181e2a409) Copyright © 2010 International Association for the Study of Lung Cancer Terms and Conditions

4 FIGURE 3 Expressions of MET and phospho-MET and their relationships with sensitivities to the MET inhibitor. The expressions of MET and phospho-MET were determined by Western blot analysis. The results were corrected for beta-actin and expressed in arbitrary units. A, Expression of MET in 41 cell lines. The protein expression of MET was consistent with the mRNA expression of MET determined by oligonucleotide array analysis (not shown). Cell lines were arranged in ascending order of their IC50 values. MET was strongly expressed in 16 cell lines (MET/beta-actin >2.0, red bars). B, Expression of phospho-MET in 41 cell lines. Phospho-MET was strongly expressed in 13 cell lines (p-MET/beta-actin >2.0, red bars). C and D, Box and whisker plots of MET (C) and phospho-MET (D) expression levels in the sensitive, intermediate, and resistant groups. E, Correlation between MET and phospho-MET expression in 41 cell lines. The results are shown in a two-way scatter plot in which the x axis indicates the expression of MET corrected for beta-actin and the y axis indicates the expression of phospho-MET corrected for beta-actin. Purple, orange, and light blue rhombuses indicate “sensitive,” “intermediate,” and “resistant” cell lines, respectively. Cell lines harboring MET amplification are surrounded by black circles. F and G, Expressions of MET (F) and phospho-MET (G) in 11 KRAS-mutated cell lines. Cell lines were arranged in ascending order of their IC50 values. Journal of Thoracic Oncology 2010 5, DOI: ( /JTO.0b013e3181e2a409) Copyright © 2010 International Association for the Study of Lung Cancer Terms and Conditions

5 FIGURE 4 The effects of PHA on the phosphorylation levels of MET, ERK, and AKT. Nine cell lines with high phospho-MET expression consisted of three sensitive cell lines (EBC1, H1993, and H1648), five resistant cell lines (HCC8227, H1975, LC-2/ad, Calu3, and H441), and one intermediate cell line (H2009). MET dephosphorylation was seen in all the cell lines tested. Dephosphorylation of ERK and AKT were seen in three of the three MET-amplified cell lines (EBC1, H1993, and H1648) and one of the two KRAS-mutant cell lines (“resistant” H441) but not in the four resistant cell lines (HCC8227, H1975, LC-2/ad, and Calu3). Journal of Thoracic Oncology 2010 5, DOI: ( /JTO.0b013e3181e2a409) Copyright © 2010 International Association for the Study of Lung Cancer Terms and Conditions

6 FIGURE 5 Expressions of E-cadherin and vimentin and their relationships with sensitivities to the MET inhibitor. A and B, Box and whisker plots showing the distribution of E-cadherin (A) and vimentin (B) gene expression levels in the sensitive, intermediate, and resistant groups. C and D, Expressions of E-cadherin (C) and vimentin (D), their relationships to the genetic statuses of MET, EGFR, HER2, and KRAS, and their sensitivities to the MET inhibitor. White bars, brown bars, and black bars indicate sensitive, intermediate, and resistant cell lines, respectively. Cell lines were arranged according to their genetic abnormalities as shown in the lower panel. METamp, MET amplification; EGFRmut, EGFR mutation; METmut, MET mutation; HER2amp, HER2 amplification; HER2mut, HER2 mutation; KRASmut, KRAS mutation. Journal of Thoracic Oncology 2010 5, DOI: ( /JTO.0b013e3181e2a409) Copyright © 2010 International Association for the Study of Lung Cancer Terms and Conditions

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