Abstract 3681: Vascular endothelial growth factor receptor tyrosine kinase inhibitor inhibited mutated epidermal growth factor receptor-driven tumors ex vivo and in vivo

We previously established a non-smoking-related lung cancer mouse model employing an epidermal growth factor receptor (EGFR) L858R transgenic mouse using an SP-C promoter. The mice developed pulmonary atypical adenomatous hyperplasia (AAH), multifocal adenocarcinoma, and died due to multiple invasive lung tumors at 4, 7, and approximately 40 weeks of age, respectively. We demonstrated the marked chemopreventive effect of gefitinib, an EGFR tyrosine kinase inhibitor, in a non-smoking-related lung cancer mouse model and presented a novel concept of molecular targeted chemoprevention of lung cancer in non-smokers. In this study, we focused on the expression of vascular endothelial growth factor receptor (VEGFR) -2 and vascular endothelial growth factor (VEGF) in a non-smoking-related lung cancer mouse model. Surprisingly, we found that VEGFR-2 and EGFR were activated in the transgenic mice at 3 weeks of age by Western blotting, before the histological detection of AAH and adenocarcinoma. And fluorescent immunostaining of lung tissues in transgenic mice showed activation of VEGFR-2 occurred in tumor cells themselves or cells in an initial stage of carcinogenesis, not only in vascular endothelial cells. We also found that VEGFR-2 was activated in the lung cancer cell lines (PC-9, H3255) harboring EGFR mutation, and that EGFR-L858R transfected 293T cells expressed more phosphorylated VEGFR-2 than non-transfected 293T cells. EGFR-L858R-transfected 293T cells were more sensitive than non-transfected 293T cells to cediranib (Recentin), a pan-VEGFR tyrosine kinase inhibitor. In this mouse model, cediranib (5 mg/kg/day, 5 days/week, 12 weeks, p.o.) inhibited surface lung tumors (long axis diameter >1 mm, 0 ± 0.4 versus 4.9 ± 3.2, p If VEGFR-2 is activated during an early phase of carcinogenesis due to EGFR mutations, these data suggest that inactivation of VEGFR-2 may be effective in preventing carcinogenesis of non-smoking-related lung cancer. These findings provide t the new concept of VEGFR-2 role in chemoprevention. Recentin (cediranib) is a trademark of the AstraZeneca group of companies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3681. doi:10.1158/1538-7445.AM2011-3681