Abstract 2859: Dual targeting of protein tyrosine kinase c-Src and protein tyrosine phosphatase SHP-2 is a novel therapeutic strategy that induces potent inhibition of pancreatic cancer cell viability in vitro and tumor progression in vivo

Abstract

Abstract Pancreatic adenocarcinoma is a deadly human malignancy, with over 95% of patients succumbing within five years. The majority of pancreatic cancer deaths are caused by metastatic dissemination of the primary tumor. The only curative treatment is surgical resection, which is limited by tumor stage, and the standard chemotherapeutic option, gemcitabine, offers only modest survival and quality of life benefits. There is a need for a greater understanding of pancreatic cancer biology and development of novel therapies to inhibit tumor progression and metastasis. The non-receptor protein tyrosine kinase, c-Src (Src) has emerged as a potential target for the treatment of pancreatic cancer, having been demonstrated to promote a number of tumorigenic processes. Src is overexpressed and/or aberrantly activated in greater than 70% of human pancreatic cancers. In addition, SHP-2, a non-receptor protein tyrosine phosphatase, regulates Src family kinase activity. Evidence has established clinical relevance for SHP-2 in human diseases. A recent study demonstrated that inhibition of SHP-2 abrogates in vitro and in vivo angiogenesis and inhibits activity of the MAPK/Erk1/2 and PI3K/Akt survival pathways. SHP-2 and Src function as key signaling intermediates downstream of growth factor receptors, cytokine receptors, and integrins, and are crucial for activation of downstream cascades of tumor progression and metastasis. The purpose of this study was to determine the importance of SHP-2 and Src, for pancreatic cancer signaling, cell biology, tumorigenicity, and metastasis. We have demonstrated elevated SHP-2 expression and phosphorylation in pancreatic cancer cells, relative to normal pancreatic cells. Phosphorylation of SHP-2 in pancreatic cancer cells occurs in a Src kinase-dependent fashion. Functional inhibition of SHP-2 and Src, individually or in combination, resulted in reduced ERK-1/2 phosphorylation, increased cleavage of caspase 3 and PARP, increased expression of the pro-apoptotic protein Bax, and decreased levels of the anti-apoptotic protein Bcl-xL. These results were mirrored by decreased viability and increased caspase activity in the presence of Src and SHP-2 inhibition. Finally, treatment of mice with small molecule inhibitors of Src or SHP-2, produced markedly smaller pancreatic tumors relative to controls in an orthotopic nude mouse model and dual treatment exacerbated this effect. The potential use for the Src and SHP-2 signaling axes as therapeutic targets remains largely untapped. These data suggest the importance of SHP-2 in pancreatic cancer cell biology and its potential value as a therapeutic target. Our studies suggest that the anti-tumor/anti-metastatic effects of Src inhibition may be improved through simultaneous inhibition of SHP-2. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2859. doi:1538-7445.AM2012-2859