title: Efficacy of the kinase inhibitor SU11248 against gastrointestinal stromal tumor mutants refractory to imatinib mesylate.
abstract: OBJECTIVE
  The majority of gastrointestinal stromal tumors harbor mutations in the receptor tyrosine kinases KIT or platelet-derived growth factor receptor A (PDGFRA), and respond to treatment with the tyrosine kinase inhibitor imatinib. Some tumors, however, show primary resistance to imatinib treatment, and most others become resistant during treatment. The most common mechanism of imatinib resistance involves specific mutations in the kinase domains of KIT or PDGFRA. We tested the activity of SU11248, an orally active small-molecule tyrosine kinase inhibitor, to inhibit important imatinib-resistant KIT and PDGFRA mutants.
  
  
  METHODS
  Primary imatinib-resistant tumor cells and cell lines expressing clinically identified imatinib-resistant KIT-V654A, KIT-T670I, or PDGFRA-D842V mutant isoforms were evaluated for sensitivity to SU11248 by Western immunoblotting and proliferation assays. Three patients with the KIT-V654A mutation were treated with SU11248.
  
  
  RESULTS
  Based on ex vivo assays, SU11248 potently inhibits KIT kinase activity of V654A and T670I mutants and suppresses proliferation of the cells expressing these mutations. Sensitivity of KIT-V654A and KIT-T670I mutants to SU11248 was confirmed using cell lines expressing these mutants. In contrast, SU11248 did not potently inhibit the PDGFRA-D842V mutant. In agreement with these results, two of the three imatinib-resistant patients with the KIT-V654A mutation responded to SU11248 treatment.
  
  
  CONCLUSIONS
  These studies suggest that SU11248 may be a useful therapeutic agent to treat gastrointestinal stromal tumors harboring the imatinib-resistant KIT-V654A or KIT-T670I mutations, but it has no effect on the activity of the PDGFRA-D842V mutant. Specific kinase inhibitors should be designed to inhibit the constitutive activating PDGFRA mutation at codon 842.
authors.affiliation: Departments of General Medical Oncology and Human Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), Leuven, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: Prenen
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: Nicole
authors.initials: N
authors.lastname: Mentens
authors.forename: Cedric
authors.initials: C
authors.lastname: Folens
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Allan
authors.initials: A
authors.lastname: Van Oosterom
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001549:Benzamides; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D000077210:Sunitinib; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D011743:Pyrimidines; D011758:Pyrroles; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D000077210:Sunitinib