Identification of aurora kinase A as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors
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Chun-Nan Yeh1,*, Chueh-Chuan Yen2,3,4,*, Yen-Yang Chen5, Chi-Tung Cheng1, Shih-Chiang Huang6, Ting-Wei Chang2, Fang-Yi Yao2, Yung-Chan Lin2, Yao-Shan Wen2, Kun-Chun Chiang7, Jen-Shi Chen8, Ta-Sen Yeh1, Cheng-Hwai Tzeng2,4, Ta-Chung Chao2,3,4, Jonathan A. Fletcher9
1 Department of Surgery, Lin-Kou Medical Center, Chang Gung Memorial Hospital and University, Gueishan Township, Taoyuan County, Taiwan
2 Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
3 Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan
4 National Yang-Ming University School of Medicine, Taipei, Taiwan
5 Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
6 Department of Pathology, Lin-Kou Medical Center, Chang Gung Memorial Hospital and University, Gueishan Township, Taoyuan County, Taiwan
7 Department of Surgery, Keelung Medical Center, Chang Gung Memorial Hospital and University, Keelung, Taiwan
8 Department of Medical Oncology, Lin-Kou Medical Center, Chang Gung Memorial Hospital and University, Gueishan Township, Taoyuan County, Taiwan
9 Department of Pathology, Brigham and Women’s Hospital, Boston, MA, U.S.A.
* CN Yeh and CC Yen contributed equally to this manuscript
Chueh-Chuan Yen, e-mail: [email protected]
Chun-Nan Yeh, e-mail: [email protected]
Keywords: aurora kinase A; gastrointestinal stromal tumor; imatinib mesylate; MLN8237
Received: December 15, 2013 Accepted: May 20, 2014 Published: May 23, 2014
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.
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