Abstract 5364: AURA kinases as markers and targets in GIST

Abstract

Abstract Mitotic index has been found to be an important prognostic factor in primary gastrointestinal stromal tumor (GIST). By using gene sets related to cell cycle (Proc Natl Acad Sci U S A. 2008; 22;105(3):955-60), we can stratify a group of patients with advanced GIST (J Clin Oncol 2008;26:4100-4108.) into two risk groups with distinct survival. So it is interesting to explore whether genes involved in regulation of cell cycle could be used as a target in treating GIST. Aurora kinase A (AURKA) and B (AURKB) were two important genes in cell cycle regulation. In the same cohort of patients, expression levels of both AURKA and AURKB were found higher in high risk group patients than those in low risk group. By using MTT assay, GIST882, an imatinib-sensitive GIST cell line, was relatively resistant to both AURKA inhibitor MLN8237 and AURKB inhibitor ZM447439 than GIST 48IM, an imatinib-resistant GIST cell line. MLN8237 could induce significant cell cycle arrest in both GIST cell lines, but apoptosis could only be seen in GIST48IM. On the other hand, after ZM447439 treatment, cell cycle inhibition could only be found in GIST48IM, and none of them had apoptosis. Instead, ZM447439 could induce autophagy in both cell lines. We then used immunohistochemistry (IHC) to examine 76 primary GIST patients. High expression of AURKA but not AURKB was more often seen in non-gastric GIST. In univariate analysis, patients with tumors having strong AURKA IHC staining, as well as large tumor size, high mitotic index and NIH high risk group, had significant lower survival than comparative groups. However, in the multivariate analysis, only high mitotic count and high AURKA expression were independent adverse prognostic factors. In conclusion, cell cycle-related genes could be used in predicting prognosis in advanced GIST, and cell cycle regulated genes such as AURKA and AURKB could be used as treatment targets. 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 5364. doi:10.1158/1538-7445.AM2011-5364