EGFR Mutation and Resistance of Non-Small-Cell Lung Cancer to Gefitinib

N Engl J Med. 2005 Feb 24;352(8):786-92. doi: 10.1056/NEJMoa044238.

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Biopsy
  • Carcinoma, Non-Small-Cell Lung / diagnosis
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • DNA, Neoplasm
  • Drug Resistance, Neoplasm / genetics*
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / chemistry
  • ErbB Receptors / genetics*
  • Erlotinib Hydrochloride
  • Gefitinib
  • Humans
  • Lung Neoplasms / diagnosis
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Male
  • Models, Structural
  • Molecular Structure
  • Neoplasm Recurrence, Local / pathology
  • Point Mutation
  • Quinazolines / adverse effects
  • Quinazolines / chemistry
  • Quinazolines / metabolism
  • Quinazolines / therapeutic use*
  • RNA, Neoplasm
  • Sequence Analysis, DNA
  • Sequence Analysis, RNA

Substances

  • Antineoplastic Agents
  • DNA, Neoplasm
  • Quinazolines
  • RNA, Neoplasm
  • Erlotinib Hydrochloride
  • ErbB Receptors
  • Gefitinib