Abstract 350: Inhibition of SHP2 impairs oncogenic activity of EGFR mutants in non-small cell lung cancer

Activating mutations of epidermal growth factor receptor (EGFR) are found in 5-15% of non small cell lung carcinomas (NSCLC) and are targets of NSCLC treatment. However, most patients treated with EGFR tyrosine kinase inhibitors eventually acquire drug resistance, pointing to the need of evaluating other molecules as potential targets for developing new therapy for NSCLC. The protein tyrosine phosphatase (PTP) SHP2 mediates signaling of growth factor receptors including that of EGFR. SHP2 is activated by EGFR mutants in lung adenocarcinoma. Inhibition of SHP2 with the SHP2 PTP inhibitor SPI-112Me or SHP2 knockdown suppressed proliferation of EGFR-dependent HCC827 and H1975 cells. To assess the role of Shp2 in the transgenic mouse model of EGFR mutant-driven lung cancer, we generated transgenic mice carrying a doxycycline (dox)-inducible, PTP-defective SHP2 (tetO-SHP2CSDA). Bitransgenic CCSP-rtTA/tetO-SHP2CSDA mice were crossed with tetO-EGFRL858R mice. F1 offspring of dox-induced transgenic mice were analyzed. Erk1/2 and Src were activated by EGFRL858R in bitransgenic CCSP-rtTA/tetO-EGFRL858R mice. Both of them were suppressed by SHP2CSDA in CCSP-rtTA/tetO-EGFRL858R/tetO-SHP2CSDA tritransgenic mice. Importantly, expression of SHP2CSDA significantly inhibited EGFRL858R-induced lung tumor in the tritransgenic mice. These results suggest that SHP2 is critical for lung tumorigenesis mediated by EGFR mutations. Citation Format: Valentina E. Schneeberger, Yuan Ren, Noreen Luetteke, Hartmut Berns, Liwei Chen, Harshani R. Lawrence, Nicholas J. Lawrence, Alex S. Lopez, Eric B. Haura, Domenico Coppola, Jie Wu. Inhibition of SHP2 impairs oncogenic activity of EGFR mutants in non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 350. doi:10.1158/1538-7445.AM2013-350