title: Identification of aurora kinase A as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors.
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.
authors.affiliation: Department of Surgery, Lin-Kou Medical Center, Chang Gung Memorial Hospital and University, Gueishan Township, Taoyuan County, Taiwan.
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Yeh
authors.forename: Chueh-Chuan
authors.initials: CC
authors.lastname: Yen
authors.forename: Yen-Yang
authors.initials: YY
authors.lastname: Chen
authors.forename: Chi-Tung
authors.initials: CT
authors.lastname: Cheng
authors.forename: Shih-Chiang
authors.initials: SC
authors.lastname: Huang
authors.forename: Ting-Wei
authors.initials: TW
authors.lastname: Chang
authors.forename: Fang-Yi
authors.initials: FY
authors.lastname: Yao
authors.forename: Yung-Chan
authors.initials: YC
authors.lastname: Lin
authors.forename: Yao-Shan
authors.initials: YS
authors.lastname: Wen
authors.forename: Kun-Chun
authors.initials: KC
authors.lastname: Chiang
authors.forename: Jen-Shi
authors.initials: JS
authors.lastname: Chen
authors.forename: Ta-Sen
authors.initials: TS
authors.lastname: Yeh
authors.forename: Cheng-Hwai
authors.initials: CH
authors.lastname: Tzeng
authors.forename: Ta-Chung
authors.initials: TC
authors.lastname: Chao
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA, U.S.A.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
mesh_terms: D064096:Aurora Kinase A / Q000627:therapeutic use*; D016922:Cellular Senescence; D018572:Disease-Free Survival; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy*; D006801:Humans; D009362:Neoplasm Metastasis; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: D064096:Aurora Kinase A