title: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib.
abstract: Mutations of the epidermal growth factor receptor (EGFR) gene have been identified in specimens from patients with non-small-cell lung cancer who have a response to anilinoquinazoline EGFR inhibitors. Despite the dramatic responses to such inhibitors, most patients ultimately have a relapse. The mechanism of the drug resistance is unknown. Here we report the case of a patient with EGFR-mutant, gefitinib-responsive, advanced non-small-cell lung cancer who had a relapse after two years of complete remission during treatment with gefitinib. The DNA sequence of the EGFR gene in his tumor biopsy specimen at relapse revealed the presence of a second point mutation, resulting in threonine-to-methionine amino acid change at position 790 of EGFR. Structural modeling and biochemical studies showed that this second mutation led to gefitinib resistance.
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
authors.forename: Susumu
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.forename: Tajhal
authors.initials: T
authors.lastname: Dayaram
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: Olivier
authors.initials: O
authors.lastname: Kocher
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eck
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Balázs
authors.initials: B
authors.lastname: Halmos
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001706:Biopsy; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D004273:DNA, Neoplasm; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008961:Models, Structural; D015394:Molecular Structure; D009364:Neoplasm Recurrence, Local / Q000473:pathology; D017354:Point Mutation; D011799:Quinazolines / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D012334:RNA, Neoplasm; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D011799:Quinazolines; D012334:RNA, Neoplasm; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib