Abstract 1237: Role of Src in resistance to anoikis in detachedpancreatic cancer cells

Abstract

Abstract Pancreatic adenocarcinoma is an aggressive malignancy currently ranked as the fourth leading cause of cancer related death in the United States, with over 95% of patients succumbing to the disease within 5 years of diagnosis. The vast majority of pancreatic cancer deaths are due to metastatic dissemination of the primary tumor. The non-receptor protein tyrosine kinase, c-Src (Src) has emerged in recent years as a potential target for pancreatic cancer treatment. In vitro studies have demonstrated the importance of Src for pancreatic tumor cell adhesion, migration, invasiveness, and resistance to apoptotic death. Mouse models of pancreatic cancer have indicated an important role for Src in formation of metastases. In addition, SHP-2, a non-receptor protein tyrosine phosphatase that regulates Src family kinase activity, has been recently shown to be a key mediator of various signaling pathways and evidence has established clinical relevance for SHP-2 in human diseases. Our goal is to determine the importance of Src for discrete steps in the progression to pancreatic cancer metastasis and resistance to detachment-induced cell death and the role of SHP-2 in modulating Src activity and downstream biology during this process. We have demonstrated a rapid and robust activation of Src in L3.6 human pancreatic cancer cells that have become detached from the extracellular environment, a crucial step in the development of metastases. Also, we have observed co-immunoprecipitation between Src and SHP-2 in detached cells, suggesting a potential role for SHP-2 in regulating Src activity in detached pancreatic cancer cells. In addition, our results reveal a Src-dependent activation of the Akt cell survival cascade and the stress kinase, Jun N-terminal kinase (JNK) in detached cells. Furthermore, this study confirmed that inhibition of both Src and SHP-2 in combination sensitizes L3.6 pancreatic cancer cells to anoikis in detached cells. We hypothesize that Src activity in detached pancreatic cancer cells promotes metastasis through suppression of anoikis. We will confirm these in vitro studies by testing the effects of inhibition of Src alone or in combination with SHP-2 inhibition on metastatic tumor formation using a nude mouse experimental metastasis model. The potential use for the Src and SHP-2 signaling axes as therapeutic targets for many cancers remains largely untapped. Our studies suggest that the anti-tumor and 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 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 1237. doi:10.1158/1538-7445.AM2011-1237