Therapeutic targets in gastrointestinal stromal tumors

作     者：Jia-Qing Zhu Wen-Bin Ou 

作者机构：College of Life Sciences Zhejiang Sci-Tech University Zhejiang Provincial Key Laboratory of Applied Enzymology Yangtze Delta Region Institute of Tsinghua University 

出 版 物：《World Journal of Translational Medicine》 (世界转化医学杂志)

年 卷 期：2015年第4卷第1期

页      面：25-37页

学科分类：10[医学] 

基　　金：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 

主　　题：Gastrointestinal stromal tumors Tyrosine kinase inhibitors KIT Platelet-derived growth factor receptorα Targets 

摘      要：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 plateletderived growth factor receptor α(PDGFRA),resultingin 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 secondline 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.