title: Novel approaches to imatinib- and sunitinib-resistant GIST.
abstract: Gastrointestinal stromal tumors (GISTs) generally arise from primary activating mutations in the KIT or PDGFRA genes that result in constitutive activation of receptor tyrosine kinase activity. Imatinib provides targeted therapy for GIST by inhibiting the KIT and PDGFR-alpha tyrosine kinases. Clinical benefit is achieved in approximately 85% of patients with unresectable or metastatic disease, with a median progression-free survival of 20 to 24 months. The mechanisms of acquired resistance to imatinib are heterogeneous, with most involving the emergence of secondary mutations in KIT exons 13, 14, or 17. In patients failing or intolerant to imatinib, the multitargeted agent sunitinib achieves durable disease control in approximately 50% of cases. Experimental treatment options beyond those currently available consist of other KIT-targeting tyrosine kinase inhibitors, such as nilotinib, or agents targeting alternative pathways, such as antiangiogenic agents, mammalian target of rapamycin, RAF kinase, and chaperone inhibitors.
authors.affiliation: Helios Klinikum Bad Saarow, Department of Hematology, Oncology, and Palliative Care, Sarcoma Center Berlin-Brandenburg, Pieskower Strasse 33, 15526 Bad Saarow, Germany. peter.reichardt@helios-kliniken.de
authors.forename: Peter
authors.initials: P
authors.lastname: Reichardt
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib
chemical_list: D020533:Angiogenesis Inhibitors; D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D000077210:Sunitinib
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