Abstract 5343: Continuing expression of SHP2E76K is required to maintain lung tumors induced by the active SHP2E76K mutant in transgenic mice

Abstract

Abstract The SHP2 protein tyrosine phosphatase is activated by growth factor receptor oncogenes or by gain-of-function (GOF) missense mutations such as SHP2E76K in human cancer. To study the oncogenic function of GOF SHP2 mutants and the dependency of SHP2 mutant-induced tumors, we established transgenic mice containing the tetO-SHP2E76K transgene. tetO-SHP2E76K mice were bred to CCSP-rtTA mice to direct expression of the transgene in type II pneumocytes to assess the role of the SHP2 mutant in lung adenocarcinoma. When the CCSP-rtTA/tetO-SHP2E76K bitransgenic mice were induced with doxycycline (dox), they developed papillary adenomas that progressed to adenocarcinoma in 6-9 months. This result demonstrates the oncogenic activity of the GOF SHP2 mutant in our mouse model of lung adenocarcinoma. Consistent with previous studies in cultured cells, lung tissues from dox-induced CCSP-rtTA/tetO-SHP2E76K have elevated pGab1, pErk, pSrc and c-Myc. Using magnetic resonance imaging (MRI), we were able to detect lung tumors in the dox-induced CCSP-rtTA/tetO-SHP2E76K bitransgenic mice. To determine if the SHP2E76K-induced lung tumors require continuing expression of the SHP2 mutant for tumor maintenance, dox was withdrawn from the CCSP-rtTA/tetO-SHP2E76K mice after detection of lung tumors by MRI. When these mice were examined again by MRI one month after dox withdrawal, the lung tumors were no longer detectable. Histological evaluation of lung tissues revealed residual hyperplastic lesions as well as evidence of necrosis, while biochemical analysis showed that pGab1, pErk, pSrc and Myc returned to basal levels. Thus, discontinuation of SHP2E76K expression resulted in tumor regression. These data indicate that continuing expression of SHP2E76K is required for maintenance of the SHP2 mutant-induced lung tumors. Citation Format: Valentina E. Schneeberger, Noreen Luetteke, Yuan Ren, Parastou Foroutan, Gary V. Martinez, Eric B. Haura, Domenico Coppola, Jie Wu. Continuing expression of SHP2E76K is required to maintain lung tumors induced by the active SHP2E76K mutant in transgenic mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5343. doi:10.1158/1538-7445.AM2014-5343