Targeted Therapy in Gastrointestinal Stromal Tumors

Abstract

Advances in the understanding of the molecular mechanisms of gastrointestinal stromal tumors (GISTs) pathogenesis have resulted in the development of a treatment approach which has become a model of targeted therapy in oncology. The introduction of imatinib mesylate [inhibiting KIT/PDGFRA (platelet-derived growth factor receptor-α) and their downstream signaling cascade] has dramatically improved the therapy of advanced (inoperable and/or metastatic) GIST. Imatinib has now become the standard of care in the treatment of patients with advanced GIST and its efficacy has been proven also in adjuvant setting after resection of primary high-risk tumors. However, a majority of patients eventually develop resistance to imatinib. Over the last few years, significant progress has been made in elucidating the mechanism of disease progression (as secondary mutations in KIT and/or PDGFRA kinase domains) and resistance to imatinib. Currently, the second-line approved drug is sunitinib—a multikinase inhibitor of KIT and PDGFRA/B and of the vascular endothelial growth factor receptors (VEGFRs)-1, -2, and 3, FMS-like tyrosine kinase-3 (FLT3), colony stimulating factor 1 receptor (CSF-1R), and glial cell-line derived neurotrophic factor receptor [Rearranged during Transfection (RET)], and in the third line, regorafenib was approved recently. However, a number of new generation tyrosine kinase inhibitors (as ponatinib) are being evaluated at present alongside treatment options alternative to inhibiting the KIT signaling pathway (as heat shock protein 90 or insulin-like growth factor 1 receptor).KeywordsGastrointestinal stromal tumorKITPDGFRImatinibSunitinibRegorafenib