Epithelial to Mesenchymal Transition in an Epidermal Growth Factor Receptor-Mutant Lung Cancer Cell Line with Acquired Resistance to Erlotinib Kenichi.

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Epithelial to Mesenchymal Transition in an Epidermal Growth Factor Receptor-Mutant Lung Cancer Cell Line with Acquired Resistance to Erlotinib Kenichi Suda, MD, Kenji Tomizawa, MD, Makiko Fujii, DDS, Hideki Murakami, MD, Hirotaka Osada, MD, Yoshihiko Maehara, MD, Yasushi Yatabe, MD, Yoshitaka Sekido, MD, Tetsuya Mitsudomi, MD Journal of Thoracic Oncology Volume 6, Issue 7, Pages 1152-1161 (July 2011) DOI: 10.1097/JTO.0b013e318216ee52 Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Establishment of HCC4006ER cells by chronic, repeated exposure to increasing concentrations of erlotinib. A, HCC4006ER cells were resistant to erlotinib. HCC4006 or HCC4006ER5 cells were incubated for 24 hours and an additional 72 hours with the indicated concentrations of erlotinib, and cell growth was assessed. B, Analysis of activated receptor tyrosine kinases (RTKs) using a Human Phospho-RTK Array Kit. Whole-cell extracts from HCC4006 and HCC4006ER5 cells exposed for 24 hours to the indicated drugs were incubated with the arrays, and phosphorylation status was determined. Each RTK was spotted in duplicate, and the pairs of dots in each corner are positive controls. C, Morphological differences observed between HCC4006 and HCC4006ER5 cells. Journal of Thoracic Oncology 2011 6, 1152-1161DOI: (10.1097/JTO.0b013e318216ee52) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Analyses of intracellular signaling pathways and epidermal growth factor receptor (EGFR) dependency in HCC4006 and HCC4006ER5 cells. A, Cells were incubated for 8 hours with the indicated concentrations of erlotinib, and changes in EGFR- or insulin-like growth factor I receptor (IGF-IR)-related signals were analyzed using Western blotting. B, Analysis of activated intracellular kinases using the Human Phospho-kinase Array Kit. Whole-cell extracts from HCC4006 and HCC4006ER5 cells exposed to 2 μM erlotinib for 8 hours were incubated with the arrays, and phosphorylation status was determined. Each kinase was spotted in duplicate and the pairs of dots in each corner (with the exception of the right-lower corner) are positive controls. C, Confirmation of EGFR knockdown using two different siRNAs. HCC4006ER5 cells were reverse-transfected with the indicated siRNA, incubated for 72 hours, and EGFR-related signals were analyzed using Western blotting. D, HCC4006ER cells were EGFR independent. HCC4006 or HCC4006ER5 cells were reverse-transfected with control siRNA or EGFR2 siRNA, incubated for 24 hours and an additional 48 hours with the indicated concentrations of erlotinib (Er.), and cell growth was assessed. Journal of Thoracic Oncology 2011 6, 1152-1161DOI: (10.1097/JTO.0b013e318216ee52) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Growth inhibitory effects of the MEK inhibitor and/or the Akt inhibitor. A–C, HCC4006 or HCC4006ER5 cells were incubated for 24 hours and an additional 72 hours with indicated concentrations (nM) of the MEK inhibitor PD0325901 (PD; A), with the Akt inhibitor AKT 1/2 Kinase Inhibitor (AKT; B), or with the combination (Comb) of both drugs (C), and cell growth was assessed. D, Cells were incubated for 8 hours with 2 μM of the indicated drug(s), and activations of Akt or ERK were analyzed using Western blotting. Journal of Thoracic Oncology 2011 6, 1152-1161DOI: (10.1097/JTO.0b013e318216ee52) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Epithelial to mesenchymal transition (EMT) and elevation of transforming growth factor beta (TGFbeta)-related signaling in HCC4006ER5 cells. A, Relative gene expression levels of several receptor tyrosine kinases (RTKs) determined using a gene expression array. HER family members were completely down-regulated in HCC4006ER5 cells. B, Loss of E-cadherin expression and up-regulation of vimentin in HCC4006ER5 cells, as assessed using Western blotting. C, Elevation of TGFbeta-related signaling in HCC4006ER5 cells, as assessed using gene-set enrichment analysis (GSEA). D, Downstream signaling of TGFbeta in HCC4006 and HCC4006ER5 cells was identified using Western blotting. Journal of Thoracic Oncology 2011 6, 1152-1161DOI: (10.1097/JTO.0b013e318216ee52) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 The histone deacetylase (HDAC) inhibitor but not the transforming growth factor beta (TGFbeta) inhibitor restored moderate sensitivity to erlotinib in HCC4006ER5 cells. A, SD208 did not restore remarkable erlotinib (Er.) sensitivity in HCC4006ER5 cells. HCC4006ER5 cells were incubated for 24 hours and an additional 72 hours with the indicated concentrations (nM) of erlotinib with/without 5 μM SD208, and cell growth was determined. B, Expression of E-cadherin and downstream signaling of EGFR in HCC4006 cells and in HCC4006ER5 cells treated with/without MS-275 and erlotinib were assessed using Western blotting. C, MS-275 restored moderate erlotinib sensitivity in HCC4006ER5 cells. HCC4006ER5 cells were incubated with/without 1 μM MS-275 for 24 hours and an additional 72 hours with indicated concentration of erlotinib (nM) with/without MS-275, and cell growth was determined. Journal of Thoracic Oncology 2011 6, 1152-1161DOI: (10.1097/JTO.0b013e318216ee52) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 6 Transforming growth factor beta (TGFbeta) treatment reduced erlotinib sensitivity in HCC4006 cells. A, Morphological changes observed in HCC4006 cells after treatment with 2 ng/ml TGFbeta for 2 weeks. B, TGFbeta induced erlotinib resistance and SD208 restored sensitivity in HCC4006 cells. HCC4006 cells or HCC4006 cells treated with TGFbeta for 2 weeks were incubated for 24 hours and an additional 72 hours with the indicated concentrations of erlotinib (Er.) with/without 5 μM SD208, and cell growth was determined. C, Downstream signaling of TGFbeta and EGFR in HCC4006 cells and in HCC4006 cells treated with TGFbeta for 2 weeks, as assessed using Western blotting. Journal of Thoracic Oncology 2011 6, 1152-1161DOI: (10.1097/JTO.0b013e318216ee52) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions