title: Epithelial to mesenchymal transition derived from repeated exposure to gefitinib determines the sensitivity to EGFR inhibitors in A549, a non-small cell lung cancer cell line.
abstract: Epithelial to mesenchymal transition (EMT) has been reported to be related with reduced sensitivity to EGFR tyrosine kinase (EGFR-TK) inhibitors. We performed this study to investigate whether this phenomenon would play a role in acquired resistance to gefitinib. In this study, we established a gefitinib-resistant subline (A549/GR), which was derived from the parental A549 cell line by chronic, repeated exposure to gefitinib. Compared with the A549 cells, the A549/GR cells were approximately 7.7-fold more resistant to gefitinib and they showed the cross-resistance against other EGFR-TK inhibitors, including CL-387,758, erlotinib and ZD6478. Phenotypic changes such as a spindle-cell shape and increased pseudopodia formation suggesting EMT was present in the A549/GR cells. These changes were accompanied by a decrease of E-cadherin and an increase of vimentin, which is a mesenchymal marker. In addition, the ability of invasion and migration was increased in the A549/GR cells. TGF-beta1 treatment for 72 h also induced EMT in the A549 cells and this transition led to resistance to gefitinib. Conversely, this was reversed through the removal of TGF-beta1. In conclusion, induction of EMT may contribute to the decreased efficacy of therapy in primary and acquired resistance to gefitinib.
authors.affiliation: Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Science, Seoul 139-706, Republic of Korea.
authors.forename: Jin Kyung
authors.initials: JK
authors.lastname: Rho
authors.forename: Yun Jung
authors.initials: YJ
authors.lastname: Choi
authors.forename: Jin Kyung
authors.initials: JK
authors.lastname: Lee
authors.forename: Baek-Yeol
authors.initials: BY
authors.lastname: Ryoo
authors.forename: Im Il
authors.initials: II
authors.lastname: Na
authors.forename: Sung Hyun
authors.initials: SH
authors.lastname: Yang
authors.forename: Cheol Hyeon
authors.initials: CH
authors.lastname: Kim
authors.forename: Jae Cheol
authors.initials: JC
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D019008:Drug Resistance, Neoplasm; D004848:Epithelium / Q000473:pathology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008648:Mesoderm / Q000473:pathology*; D009361:Neoplasm Invasiveness; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D053773:Transforming Growth Factor beta1; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib