Published online Apr 12, 2015. doi: 10.5528/wjtm.v4.i1.25
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
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.
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.