A mouse model system was developed for the rapid chemical induction of lung adenocarcinomas and T-cell lymphomas. Tumors are induced by transplacental injection of 1-ethyl-1-nitrosourea, followed by tumor promotion with butylated hydroxytoluene. Lung adenocarcinomas develop in 100% of offspring and 70% have additional T-cell lymphomas. Vaccination of these animals with purified Raf protein effectively doubles the time required for these animals to succumb to tumor-induced mortality. Examination of tumors for altered expression or structure of a panel of oncogenes associated with lung tumors revealed consistent mutations of c- raf-1 within a highly immunogenic region of the kinase domain. Three mutations were tested in cell culture and found to activate kinase and transforming activity. This is the first example of point-mutated c-raf-1 in vivo, demonstrating a new class of raf mutations that may also occur in human tumors. Further characterization of these mutations should allow us to generate even more effective anti-tumor regimens.
