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

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 (EGFR ⌬L747-S752 ) or the L858R mutant (EGFR L858R ) 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 EGFR L858R allele show diffuse lung cancer highly reminiscent of human bronchioloalveolar carcinoma and later develop interspersed multifocal adenocarcinomas. In contrast, mice expressing EGFR ⌬L747-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.[Keywords: EGFR; lung adenocarcinoma; mice; tyrosine kinase inhibitor] Supplemental material is available at http://www.genesdev.org.

Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer?

“…Two groups of researchers have recently developed transgenic mice that express either exon 19 deletion mutant or the L858R mutant in type II pneumocytes under the control of doxycycline (Ji et al, 2006;Politi et al, 2006). Expression of either EGFR mutant leads to the development of adenocarcinoma similar to human bronchioloalveolar cell carcinoma and withdrawal of doxycycline to reduce expression of transgene or erlotinib treatment resulted in tumour regression.…”

Acquired resistance of lung adenocarcinoma to EGFR-tyrosine kinase inhibitors gefitinib and erlotinib

“…28 Other studies found that the catalytic efficiency (k cat /K M ) of the L858R mutant is ∼20-fold higher than that of the wild-type kinase domain, suggesting that the wild-type kinase domain is autoinhibited and the L858R mutant is constitutively active. 29 Using transgenic mice, Politi et al 30 found that in type II pneumocytes, expression of either the E746-A750del mutant or the L858R mutant leads to the development of an adenocarcinoma similar to human bronchioalveolar cell carcinoma. These experiments suggest that persistent EGFR signaling underlies tumor development in human lung adenocarcinomas expressing EGFR mutants, and likely explain the sensitivity of these tumors to TKIs.…”

Epithelial NF-κB signaling promotes EGFR-driven lung carcinogenesis via macrophage recruitment

“…tet-O-EGFR L858R mice, 19 tet-O-EGFR L858RCT790M mice 24 (gifts from Dr. William Pao, Vanderbilt University), tet-O-IkBa-DN mice, 20 and CCSP-rtTA mice 37 and genotyping procedures have all been previously described. EGFR L858R and EGFR L/T transgenic mice were generated by mating tet-O-EGFR L858R or tet-O-EGFR L858RCT790M mice to homozygous CCSP-rtTA mice.…”

“…In this model, transgenic mice harbor a dox-inducible human EGFR L858R construct and the Clara cell secretory protein (CCSP) promoter-driven reverse tetracycline transactivator (CCSP-rtTA; tet-O-EGFR L858R ) so that EGFR L858R is expressed specifically in the airway epithelium when given dox (designated EGFR L858R mice). 19 To inhibit epithelial NF-kB signaling in the lungs of these mice, EGFR L858R mice were mated to transgenic mice that express a dox-inducible dominant negative IkBa (DN-IkB). 20 This DN-IkB is unable to be phosphorylated and degraded, thereby blocking translocation of the NF-kB heterodimers into the nucleus and preventing target gene transcription.…”