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

摘要: Somatic mutations in exons encoding the tyrosine kinase domain of epidermal growth factor receptor (EGFR) gene are found human lung adenocarcinomas and associated with sensitivity to inhibitors gefitinib erlotinib. Nearly 90% EGFR either short, in-frame deletions exon 19 or point that result substitution arginine for leucine at amino acid 858 (L858R). To study further role these initiation maintenance cancer, we have developed transgenic mice express an deletion mutant (EGFR(DeltaL747-S752)) L858R (EGFR(L858R)) type II pneumocytes under control doxycycline. Expression leads development adenocarcinomas. Two weeks after induction doxycycline, EGFR(L858R) allele show diffuse cancer highly reminiscent bronchioloalveolar carcinoma later develop interspersed multifocal In contrast, expressing EGFR(DeltaL747-S752) tumors embedded normal parenchyma a longer latency. With carrying allele, withdrawal doxycycline (to reduce expression transgene) treatment erlotinib inhibit activity) causes rapid tumor regression, as assessed by magnetic resonance imaging histopathology, demonstrating is required maintenance. These models may be useful developing improved therapies patients cancers bearing mutations.