title: Mechanisms of resistance to imatinib and sunitinib in gastrointestinal stromal tumor.
abstract: Gastrointestinal stromal tumor (GIST), the most common mesenchymal neoplasm of the GI tract and one of the most common sarcomas, is dependent on the expression of the mutated KIT or platelet-derived growth factor receptor in most cases. Imatinib mesylate potently abrogates the effects of KIT signaling by directly binding into the ATP-binding pocket of the kinase. It is becoming increasingly apparent that the binding affinity of imatinib for the receptor is dependent on the type and location of mutation. Within KIT, patients whose tumor has an exon 9 mutation are treated by many clinicians with higher doses of imatinib than those patients with mutations within exon 11. Additionally, there are over 400 unique mutations within exon 11 that may have distinctly different binding affinity for imatinib as well as other kinases. Secondary KIT mutations generally occur at a codon where imatinib binds resulting in KIT reactivation and resistance. Sunitinib malate, a second-generation KIT inhibitor is active in imatinib-resistant disease and is FDA-approved for use in this setting. In this review, we describe the biology of the genes and gene mutations responsible for GIST and discuss known and potential clinical implications.
authors.affiliation: Departments of Pathology, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Wei-Lien
authors.initials: WL
authors.lastname: Wang
authors.forename: Anthony
authors.initials: A
authors.lastname: Conley
authors.forename: David
authors.initials: D
authors.lastname: Reynoso
authors.forename: Laura
authors.initials: L
authors.lastname: Nolden
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.forename: Suzanne
authors.initials: S
authors.lastname: George
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Trent
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy*; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009154:Mutation / Q000502:physiology; D010879:Piperazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000502:physiology; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011758:Pyrroles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000502:physiology; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D000077210:Sunitinib