Identification of aurora kinase A as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors.

Chun-Nan Yeh,Shih-Chiang Huang,Yung-Chan Lin,Yao-Shan Wen,Ta-Sen Yeh,Yen-Yang Chen,Jonathan A Fletcher,Ta-Chung Chao,Cheng-Hwai Tzeng,Kun-Chun Chiang,Chueh-Chuan Yen,Chi-Tung Cheng,Fang-Yi Yao,Ting-Wei Chang,Jen-Shi Chen

doi:10.18632/oncotarget.1705

Abstract

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 aimed to evaluate the significance of AURKA expression as an unfavorable prognostic marker for advanced GISTs, and provide evidence that AURKA could be a potential therapeutic target in GISTs. The prognostic significance of the expression of AURKA, along with other clinicopathological factors, was analyzed in a cohort of 99 IM-treated patients with advanced GISTs. The potential use of an inhibitor of AURKA as a therapeutic agent against GISTs was also tested in GIST cell lines. Among 99 enrolled patients, poor performance status, large tumor size, drug response, and AURKA overexpression were independent prognostic factors for poor 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, inhibited growth of both IM-sensitive and IM-resistant GIST cells in a concentration-dependent manner, and exhibited synergistic cytotoxicity with IM in GIST cells. The inhibitory effect of MLN8237 in GIST cells could be attributed to the induction of G2/M arrest, apoptosis, and senescence. Our study shows that AURKA expression independently predicted poor PFS and OS in patients with advanced GISTs who were treated with IM. An AURKA inhibitor may have potential as a therapeutic agent for both IM-sensitive and IM-resistant GISTs.

Highlights

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract
Our study shows that aurora kinase A (AURKA) expression independently predicted poor progressionfree survival (PFS) and overall survival (OS) in patients with advanced gastrointestinal stromal tumors (GISTs) who were treated with imatinib mesylate (IM)
We found that overexpression of AURKA was an independent poor prognostic factor for both PFS and OS among 99 patients with advanced GISTs who were treated with IM

Summary

Introduction

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. These tumors occur most frequently in the stomach (~50%) and small intestine (25%−35%), and less frequently in the colorectal region (10%−12%), omentum/ mesentery (7%), and esophagus (1%−5%) [1,2,3]. With the development of imatinib mesylate (IM; Novartis Pharmaceuticals, Basel, Switzerland), a potent tyrosine kinase inhibitor (TKI) that inhibits both KIT and PDGFRA, the median overall survival (OS) of patients with advanced GISTs has improved from less than one year in the pre-TKI era to five to six years. There is an urgent need to identify new biomarkers and/or therapeutic targets that can be used to treat these patients

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