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

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 c...

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Main Authors:	Yeh, Chun-Nan, Yen, Chueh-Chuan, Chen, Yen-Yang, Cheng, Chi-Tung, Huang, Shih-Chiang, Chang, Ting-Wei, Yao, Fang-Yi, Lin, Yung-Chan, Wen, Yao-Shan, Chiang, Kun-Chun, Chen, Jen-Shi, Yeh, Ta-Sen, Tzeng, Cheng-Hwai, Chao, Ta-Chung, Fletcher, Jonathan A.
Format:	Online
Language:	English
Published:	Impact Journals LLC 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147307/

id	pubmed-4147307
recordtype	oai_dc
spelling	pubmed-41473072014-08-29 Identification of aurora kinase A as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors Yeh, Chun-Nan Yen, Chueh-Chuan Chen, Yen-Yang Cheng, Chi-Tung Huang, Shih-Chiang Chang, Ting-Wei Yao, Fang-Yi Lin, Yung-Chan Wen, Yao-Shan Chiang, Kun-Chun Chen, Jen-Shi Yeh, Ta-Sen Tzeng, Cheng-Hwai Chao, Ta-Chung Fletcher, Jonathan A. Research Paper 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. Impact Journals LLC 2014-06-02 /pmc/articles/PMC4147307/ /pubmed/24901229 Text en Copyright: © 2014 Yeh et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Yeh, Chun-Nan Yen, Chueh-Chuan Chen, Yen-Yang Cheng, Chi-Tung Huang, Shih-Chiang Chang, Ting-Wei Yao, Fang-Yi Lin, Yung-Chan Wen, Yao-Shan Chiang, Kun-Chun Chen, Jen-Shi Yeh, Ta-Sen Tzeng, Cheng-Hwai Chao, Ta-Chung Fletcher, Jonathan A.
spellingShingle	Yeh, Chun-Nan Yen, Chueh-Chuan Chen, Yen-Yang Cheng, Chi-Tung Huang, Shih-Chiang Chang, Ting-Wei Yao, Fang-Yi Lin, Yung-Chan Wen, Yao-Shan Chiang, Kun-Chun Chen, Jen-Shi Yeh, Ta-Sen Tzeng, Cheng-Hwai Chao, Ta-Chung Fletcher, Jonathan A. Identification of aurora kinase A as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors
author_facet	Yeh, Chun-Nan Yen, Chueh-Chuan Chen, Yen-Yang Cheng, Chi-Tung Huang, Shih-Chiang Chang, Ting-Wei Yao, Fang-Yi Lin, Yung-Chan Wen, Yao-Shan Chiang, Kun-Chun Chen, Jen-Shi Yeh, Ta-Sen Tzeng, Cheng-Hwai Chao, Ta-Chung Fletcher, Jonathan A.
author_sort	Yeh, Chun-Nan
title	Identification of aurora kinase A as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors
title_short	Identification of aurora kinase A as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors
title_full	Identification of aurora kinase A as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors
title_fullStr	Identification of aurora kinase A as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors
title_full_unstemmed	Identification of aurora kinase A as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors
title_sort	identification of aurora kinase a as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors
description	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.
publisher	Impact Journals LLC
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147307/
_version_	1613128558523187200

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

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