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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Transl Med. Apr 12, 2015; 4(1): 25-37
Published online Apr 12, 2015. doi: 10.5528/wjtm.v4.i1.25
Therapeutic targets in gastrointestinal stromal tumors
Jia-Qing Zhu, Wen-Bin Ou
Jia-Qing Zhu, Wen-Bin Ou, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
Wen-Bin Ou, Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing 314006, Zhejiang Province, China
Author contributions: Zhu JQ preformed research, analyzed data, consulted literatures and wrote the paper; Ou WB consulted literatures, provided ideas, designed research, contributed new reagents, analyzed data, and wrote the paper.
Supported by The Special Project of Zhejiang Province, No. 2012C03007-4; Zhejiang Public Technology Research Program, No. 2014C33234; Zhejiang Provincial Top Key Discipline of Biology, and Science Foundation of Zhejiang Sci-Tech University, No. 14042107-Y.
Conflict-of-interest: These authors declare no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Wen-Bin Ou, College of Life Sciences, Zhejiang Sci-Tech University, 866 Yuhangtang Road, Hangzhou 310018, Zhejiang Province, China. ouwenbin@tsinghua.org.cn
Telephone: +86-573-82582765 Fax: +86-573-82582765
Received: July 26, 2014
Peer-review started: July 27, 2014
First decision: September 1, 2014
Revised: September 14, 2014
Accepted: November 27, 2014
Article in press: December 1, 2014
Published online: April 12, 2015
Processing time: 262 Days and 11.9 Hours
Abstract

Gastrointestinal stromal tumors (GISTs) are the most common type of mesenchymal tumor of the gastrointestinal tract. The tumorigenesis of GISTs is driven by gain-of-function mutations in KIT or platelet-derived growth factor receptor α (PDGFRA), resulting in constitutive activation of the tyrosine kinase and its downstream signaling pathways. Oncogenic KIT or PDGFRA mutations are compelling therapeutic targets for the treatment of GISTs, and the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with metastatic GISTs. However, most GIST patients develop clinical resistance to imatinib and other tyrosine kinase inhibitors. Five mechanisms of resistance have been characterized: (1) acquisition of a secondary point mutation in KIT or PDGFRA; (2) genomic amplification of KIT; (3) activation of an alternative receptor tyrosine kinase; (4) loss of KIT oncoprotein expression; and (5) wild-type GIST. Currently, sunitinib is used as a second-line treatment for patients after imatinib failure, and regorafenib has been approved for patients whose disease is progressing on both imatinib and sunitinib. Phase II/III trials are currently in progress to evaluate novel inhibitors and immunotherapies targeting KIT, its downstream effectors such as phosphatidylinositol 3-kinase, protein kinase B and mammalian target of rapamycin, heat shock protein 90, and histone deacetylase inhibitor. Other candidate targets have been identified, including ETV1, AXL, insulin-like growth factor 1 receptor, KRAS, FAS receptor, protein kinase c theta, ANO1 (DOG1), CDC37, and aurora kinase A. These candidates warrant clinical evaluation as novel therapeutic targets in GIST.

Keywords: Gastrointestinal stromal tumors; Tyrosine kinase inhibitors; KIT; Platelet-derived growth factor receptor α; Targets

Core tip: Oncogenic KIT and platelet-derived growth factor receptor α (PDGFRA) mutations are compelling therapeutic targets in gastrointestinal stromal tumors (GISTs), and the KIT/PDGFRA kinase inhibitors imatinib, sunitinib, and regorafenib are the standards of care for patients with unresectable or metastatic GIST. However, most patients eventually develop resistance to these kinase inhibitors, resulting in an urgent need to identify biologically rational targets for novel therapies. Herein, we review advances in the research on GIST and the therapies that are used to treat it. Additionally, we discuss novel agents, targets, and strategies for the future treatment of GIST.