title: Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255.
abstract: Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) have recently been described in patients with non-small-cell lung cancer (NSCLC) who achieve radiographic regressions to the EGFR inhibitor gefitinib. One of these mutations, L858R (Leu-->Arg), is also found in NSCLC cell line H3255, which is very sensitive to gefitinib treatment. We characterized nine NSCLC cell lines (three isolated from patients with bronchioloalveolar carcinoma and six isolated from patients with adenocarcinoma) for their in vitro sensitivity to gefitinib. Of these, only H3255 (EGFR(L858R)) and H1666 (EGFR(WT)) are sensitive to gefitinib with IC(50) values of 40 nmol/L and 2 micromol/L, respectively. We examined the effects of gefitinib on H3255 and cell lines containing wild-type EGFR that are either sensitive (H1666) or resistant (A549 and H441) to gefitinib exposure in vitro. Gefitinib treatment (1 micromol/L) leads to significant apoptosis accompanied by increased poly(ADP-ribose) polymerase cleavage only in the H3255 cell line, leads to G(1)-S arrest in H1666, and has no effects in the A549 and H441 cell lines. Although EGFR and AKT are constitutively phosphorylated in H3255, H1666, and H441 cell lines, AKT is completely inhibited by gefitinib treatment only in the H3255 cell line. These findings further characterize a mechanism by which gefitinib treatment of NSCLC harboring EGFR(L858R) leads to a dramatic response to gefitinib.
authors.affiliation: Lowe Center for Thoracic Oncology and Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Tracy
authors.forename: Toru
authors.initials: T
authors.lastname: Mukohara
authors.forename: Mark
authors.initials: M
authors.lastname: Hansen
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D066246:ErbB Receptors; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3; D000077156:Gefitinib