Targeted therapies in gastrointestinal stromal tumors

The discovery of constitutive KIT activation as the central mechanism of gastrointestinal stromal tumor (GIST) pathogenesis suggested that inhibiting or blocking KIT signaling might be the milestone in the targeted therapy of GISTs. Indeed, imatinib mesylate inhibits KIT kinase activity and represents the front-line drug for the treatment of unresectable and metastatic GISTs. Despite a high rate of response in patients with KIT exon 11 mutated GISTs, the failure rate is significantly higher in patients with a wild-type genotype, suggesting an alternative activated pathway not targeted by imatinib therapy. 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 inhibitors monotherapies. This review article summarizes the recent knowledge accumulated on targeted therapy in GIST, based on the central role of KIT oncogenic activation and subsequent signal transduction in the pathogenesis of GIST. In addition, we provide an updated discussion on diagnostic pitfalls, including changes secondary to imatinib response and resistance.