Curr Top Microbiol
-
Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the intestinal tract. Nearly all tumors have a mutation in the KIT or, less often, platelet-derived growth factor receptor (PDGFRA) or B-rapidly Accelerated Fibrosarcoma (BRAF) gene. The discovery of constitutive KIT activation as the central mechanism of GIST pathogenesis, suggested that inhibiting or blocking KIT signaling might be the milestone in the targeted therapy of GISTs. ⋯ The most common mechanism of resistance is through polyclonal acquisition of second site mutations in the kinase domain, which highlights the future therapeutic challenges in salvaging these patients after failing kinase inhibitor monotherapies. More recently, sunitinib (Sutent, Pfizer, New York, NY), which inhibits vascular endothelial growth factor receptor (VEGFR) in addition to KIT and PDGFRA, has proven efficacious in patients who are intolerant or refractory to imatinib. This review summarizes the recent knowledge on targeted therapy in GIST, based on the central role of KIT oncogenic activation, as well as discussing mechanisms of resistance.