Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors

Katerina Politi, Maureen F. Zakowski, Pang Dian Fan, Emily A. Schonfeld, William Pao, Harold E. Varmus

Research output: Contribution to journalArticlepeer-review

403 Scopus citations

Abstract

Somatic mutations in exons encoding the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are found in human lung adenocarcinomas and are associated with sensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib. Nearly 90% of the EGFR mutations are either short, in-frame deletions in exon 19 or point mutations that result in substitution of arginine for leucine at amino acid 858 (L858R). To study further the role of these mutations in the initiation and maintenance of lung cancer, we have developed transgenic mice that express an exon 19 deletion mutant (EGFRΔL747-S752) or the L858R mutant (EGFRL858R) in type II pneumocytes under the control of doxycycline. Expression of either EGFR mutant leads to the development of lung adenocarcinomas. Two weeks after induction with doxycycline, mice that express the EGFRL858R allele show diffuse lung cancer highly reminiscent of human bronchioloalveolar carcinoma and later develop interspersed multifocal adenocarcinomas. In contrast, mice expressing EGFRΔL747-S752 develop multifocal tumors embedded in normal lung parenchyma with a longer latency. With mice carrying either EGFR allele, withdrawal of doxycycline (to reduce expression of the transgene) or treatment with erlotinib (to inhibit kinase activity) causes rapid tumor regression, as assessed by magnetic resonance imaging and histopathology, demonstrating that mutant EGFR is required for tumor maintenance. These models may be useful for developing improved therapies for patients with lung cancers bearing EGFR mutations.

Original languageEnglish
Pages (from-to)1496-1510
Number of pages15
JournalGenes and Development
Volume20
Issue number11
DOIs
StatePublished - 1 Jun 2006
Externally publishedYes

Keywords

  • EGFR
  • Lung adenocarcinoma
  • Mice
  • Tyrosine kinase inhibitor

Fingerprint

Dive into the research topics of 'Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors'. Together they form a unique fingerprint.

Cite this