Recent Study on Therapeutic Targets in Gastrointestinal Stromal Tumors

Abstract

Gastrointestinal stromal tumours (GISTs) are the most prevalent kind of gastrointestinal mesenchymal tumour . Gain-of-function mutations in KIT or plateletderived growth factor receptor (PDGFRA) cause the carcinogenesis of GISTs, resulting in constitutive activation of the tyrosine kinase and its downstream signalling cascades. The KIT/PDGFRA inhibitor imatinib is the standard of therapy for patients with metastatic GISTs, and oncogenic KIT or PDGFRA mutations are attractive therapeutic targets for the treatment of GISTs. However, clinical resistance to imatinib and other tyrosine kinase inhibitors develops in the majority of GIST patients. 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. Sunitinib is being used as a second-line therapy for individuals who have failed imatinib, and regorafenib has been approved for patients who have failed 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. ETV1, AXL, insulin-like growth factor 1 receptor, KRAS, FAS receptor, protein kinase c theta, ANO1 (DOG1), CDC37, and aurora kinase A have all been identified as potential targets. These candidates should be tested in the clinic as potential new GIST treatment targets.