Abstract 2771: HSP90 inhibitor NVP-AUY922 exhibits the potent antiproliferative effect in gastrointestinal cancer cells with a lack of PTEN expression

Abstract

Abstract Background: The heat shock protein 90 (HSP90), a molecular chaperone, has provoked great interest as a promising molecular target for cancer treatment, since it is involved in regulating the conformation, stability and functions of key oncogenic proteins. At present, a variety of chemical compounds targeting HSP90 have been developed and have shown convincing anti-neoplastic activity in various preclinical tumor models. Several inhibitors of HSP90 have been reported exhibiting more antitumor efficacy in PTEN-null tumor xenograft. The aim of our study was to evaluate the antitumor effects of a novel HSP90 inhibitor, NVP-AUY922, in human malignant cells, especially in PTEN-null cancer cells. Materials and Methods: Human esophageal cancer (TE-1, TE-4, TE-8, TE-10), gastric cancer (NUGC-3, NUGC-3/IL), pancreatic cancer (PANC-1, MIAPACA-2, Bxpc3) and mutant c-kit-driven lymphocytes (Ba/F3-KE11, Ba/F3-K642, Ba/F3-820Mz), mimicking gastrointestinal stromal tumor cells, were examined. WST assay and/or trypan blue exclusion assay were conducted to assess the anti-proliferation effects of NVP-AUY922 in those cells mentioned above. The activity of cell growth-related molecules such as AKT, ERK, and PTEN were investigated by western blot analysis. Genetic modification using siRNA and expression vector were applied for silencing and overexpression of PTEN, respectively, in cancer cells. Results: Cell viability assays showed that NVP-AUY922 potently inhibits the proliferation of human cancer cell lines, regardless of 5-FU resistance or c-Kit mutation, by which the sensitivity to imatinib can be affected. PTEN-null TE-4 cells exhibited more sensitivity to NVP-AUY922. Interestingly, The sensitivity to NVP-AUY922 was increased by silencing PTEN expression in intact PTEN-expressing TE-10 cells and decreased by exogenous transduction of PTEN in TE-4 cells. Furthermore, NVP-AUY922 significantly inhibited the activity of AKT and ERK in TE-4 cells, but not in TE-10 cells. Conclusion: Inhibition of Hsp90 function by NVP-AUY922 exhibited strong cytotoxicity against most of the cancer cells, including some anticancer drug-resistant cells, revealing its potential for a novel therapeutic alternative to cancer treatment. In addition, this study suggests that the expression status of PTEN determines the sensitivity to HSP90 inhibitor for cancer treatment. 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 2771. doi:1538-7445.AM2012-2771