Abstract 3588: Antitumor activity of saracatinib, a c-Src/Abl kinase inhibitor, in gastric cancer
Authors: Hyun-Jin Nam, Do-Youn Oh, Seock-Ah Im, Hwang-Phill Kim, Young-Kwang Yoon, Ah-Rum Min, Sang-Hyun Song, Sae-Won Han, Tae-You Kim, Yung-Jue Bang
Journal: Cancer Research (2011)

Abstract Background: Src is a nonreceptor tyrosine kinase involved in the crosstalk and mediation of many signaling pathways that promote cell proliferation, adhesion, invasion, migration, metastasis, angiogenesis, and tumorigenesis. Elevation of Src activity has been reported in many types of human cancers. Therefore, Src has been promising therapeutic target for the treatment of cancers. However, the mechanism of Src inhibition in gastric cancers has not been fully understood yet. Saracatinib is an orally active small molecule c-Src/abl kinase inhibitor currently in phase II clinical trials. The purpose of this study is to evaluate the therapeutic potential of saracatinib alone or in combination with chemotherapeutic agents for the treatment of gastric cancers by testing its in vitro and in vivo efficacy. Methods: Experiments were conducted in human gastric cancer cell lines from the Korea Cell Line Bank or the American Type Culture Collection. MTT assay was used for determining growth inhibitory effect of saracatinib alone or in combination with chemotherapeutic agents (5-FU, cisplatin). Cell cycle distribution was analyzed by FACS Calibur flow cytometer and apoptotic effect was measured by annexin V assay. Western blot analysis was performed to verify molecular mechanism of this compound. The methods described by Chou and Talalay were used to determine if a synergistic effect existed. The analysis of the median effect was conducted using the Calcusyn software to determine a combination index value. (CI&amp;gt;1: antagonistic effect, CI=1:additive effect, CI&amp;lt;1: synergistic effect). NCI N87 xenograft model was used to see antitumor effect of saracatinib alone or in combination with 5-FU. Results: Saracatinib specifically inhibited the growth of SNU216 and NCI N87 cells among 10 gastric cancer cell lines. We found that saracatinib induces G1 arrest and apoptosis in sensitive cell lines. The apoptotic process required induction of the proapoptotic BH3-only BCL2 family member, BIM, and saracatinib led to increase in the BIM level in SNU216 and N87 cells. Knockdown of BIM using siRNA decreased the apoptotic cell numbers induced by treatment of saracatinib suggesting important role for BIM in saracatinib induced apoptosis pathway. The sensitivity to saracatinib in SNU216 and N87 cell lines was correlated with inhibiton of AKT and ERK pathways and blockade of HER family kinases. Furthermore, the combined treatment of saracatinib with 5-FU or cisplatin exerted synergistic effects in gastric cancer cell lines including NCI N87 cells. Consistent with these in vitro findings, saracatinib alone or in combination with 5-FU showed antitumor activity in a NCI-N87 xenograft model. Conclusion: Taken together, these preclinical evaluations support that Src is a potential therapeutic target in gastric cancer and clinical development of saracatinib alone or in combination with chemotherapy in gastric cancer could be considered. 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 3588. doi:10.1158/1538-7445.AM2011-3588