Lung adenocarcinomas induced in mice by mutant EGF receptors foundin human lung cancers respondto a tyrosine kinase inhibitor orto down-regulation of the receptors

EGFR
  1. Katerina Politi1,4,
  2. Maureen F. Zakowski2,
  3. Pang-Dian Fan1,
  4. Emily A. Schonfeld1,
  5. William Pao3, and
  6. Harold E. Varmus1
  1. 1 Program in Cancer Biology and Genetics,
  2. 2 Department of Pathology, and the
  3. 3 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA

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.

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