title: The gefitinib-sensitizing mutant epidermal growth factor receptor enables transformation of a mouse fibroblast cell line.
abstract: A specific inhibitor of the Epidermal Growth Factor Receptor (EGFR), Gefitinib, displays significant antitumor effects against non-small cell lung cancers (NSCLC) that express EGFR with mutations in their tyrosine kinase domain. Although previous reports have already demonstrated that oncogenic transformation can be induced by some mutant EGFR forms, the precise differences between mutant and wild-type EGFR in terms of mechanisms of transformation have not been fully elucidated. We show here that a murine fibroblast cell line, NR6 becomes transformed by an expression level of the mutant EGFR form lacking E746-A750 that is far less than that needed with transfected wild-type EGFR. However, the mutant EGFR was unable to transform NR6 in a ligand-independent manner, as was seen with the wild-type EGFR. The consequent biological features after transformation, including DNA synthesis or cell cycle progression and biochemical characteristics such as MAPK activation mediated by the mutant EGFR are comparable and equivalent to those mediated by wild-type EGFR. These data suggest that the mutant EGFR possesses greater ligand-dependent transformation when compared with wild-type EGFR, although the exact mechanisms to account for this characteristic remain to be defined.
authors.affiliation: Department of Respiratory Medicine, Allergy, and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Nagatomo
authors.forename: Toru
authors.initials: T
authors.lastname: Kumagai
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Yamadori
authors.forename: Mitsugi
authors.initials: M
authors.lastname: Furukawa
authors.forename: Ryo
authors.initials: R
authors.lastname: Takahashi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yoneda
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Ogata
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Saito
authors.forename: Koji
authors.initials: K
authors.lastname: Inoue
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yano
authors.forename: Takashi
authors.initials: T
authors.lastname: Kijima
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yoshida
authors.forename: Tadashi
authors.initials: T
authors.lastname: Osaki
authors.forename: Isao
authors.initials: I
authors.lastname: Tachibana
authors.forename: Mark I
authors.initials: MI
authors.lastname: Greene
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawase
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects*; D000077156:Gefitinib; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D011799:Quinazolines / Q000494:pharmacology*; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D004247:DNA; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D000077156:Gefitinib