Abstract 1309: Identification of aurora kinase a as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors

Abstract

Abstract Purpose: Although imatinib mesylate (IM) has revolutionized the management of gastrointestinal stromal tumors (GISTs), drug resistance remains a challenge. Previous studies have shown that the expression of aurora kinase A (AURKA) predicts recurrence in patients with primary surgically-resected GISTs. The current study aims to evaluate the significance of AURKA as an unfavorable prognostic marker for advanced GISTs, and provides evidence that AURKA could be a potential treatment target of GISTs. Experimental Design: The prognostic significance of AURKA, along with other clinicopathological factors, was analyzed in a cohort of 99 IM-treated patients with advanced GISTs using immunohistochemistry. The potential use of an AURKA inhibitor as therapeutic agent against GISTs was also tested in GIST cell lines. Results: Among 99 enrolled patients, poor performance status, large tumor size, drug response, and AURKA overexpression were independent poor prognostic factors for progression-free survival (PFS). For overall survival (OS), only large tumor size and AURKA overexpression were identified as independent unfavorable factors. In an in vitro study, MLN8237, an AURKA inhibitor, was demonstrated to inhibit growth of both IM-sensitive and IM-resistant GIST cells in a concentration-dependent manner. The inhibitory effect of MLN8237 on GIST cells could be attributed to the induction of G2/M arrest, apoptosis, and senescence, possibly through up-regulation of pro-apoptotic proteins. Conclusions: Our study showed that AURAK is an independent poor prognostic factor for both PFS and OS in patients with advanced GISTs treated with IM. AURKA inhibitor could be used as therapeutic agent for both IM-sensitive and IM-resistant GISTs. Citation Format: Chun-Nan Yeh, Chueh-Chuan Yen, Yeng-Yang Chen, Chi-Tung Cheng, Shih-Chiang Huang, Ting-Wei Chang, Fang-Yi Yao, Yung-Chan Lin, Yao-Shan Wen, Kun-Chun Chiang, Jen-Shi Chen, Ta-Sen Yeh, Cheng-Hwai Tzeng, Ta-Chung Chao, Jonathan A. Fletcher. Identification of aurora kinase a as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1309. doi:10.1158/1538-7445.AM2014-1309