title: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor.
abstract: OBJECTIVE
  Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. The relationship between mutations in these kinases and clinical response to imatinib was examined in a group of patients with advanced GIST.
  
  
  METHODS
  GISTs from 127 patients enrolled onto a phase II clinical study of imatinib were examined for mutations of KIT or PDGFRA. Mutation types were correlated with clinical outcome.
  
  
  RESULTS
  Activating mutations of KIT or PDGFRA were found in 112 (88.2%) and six (4.7%) GISTs, respectively. Most KIT mutations involved exon 9 (n = 23) or exon 11 (n = 85). All KIT mutant isoforms, but only a subset of PDGFRA mutant isoforms, were sensitive to imatinib, in vitro. In patients with GISTs harboring exon 11 KIT mutations, the partial response rate (PR) was 83.5%, whereas patients with tumors containing an exon 9 KIT mutation or no detectable mutation of KIT or PDGFRA had PR rates of 47.8% (P =.0006) and 0.0% (P <.0001), respectively. Patients whose tumors contained exon 11 KIT mutations had a longer event-free and overall survival than those whose tumors expressed either exon 9 KIT mutations or had no detectable kinase mutation.
  
  
  CONCLUSIONS
  Activating mutations of KIT or PDGFRA are found in the vast majority of GISTs, and the mutational status of these oncoproteins is predictive of clinical response to imatinib. PDGFRA mutations can explain response and sensitivity to imatinib in some GISTs lacking KIT mutations.
authors.affiliation: R&D-19 3710 SW US Veterans Hospital Rd, Portland, OR 97207, USA. heinrich@ohsu.edu
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Corless
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Charles D
authors.initials: CD
authors.lastname: Blanke
authors.forename: Margaret
authors.initials: M
authors.lastname: von Mehren
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.forename: Laura S
authors.initials: LS
authors.lastname: McGreevey
authors.forename: Chang-Jie
authors.initials: CJ
authors.lastname: Chen
authors.forename: Annick D
authors.initials: AD
authors.lastname: Van den Abbeele
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Beate
authors.initials: B
authors.lastname: Kiese
authors.forename: Burton
authors.initials: B
authors.lastname: Eisenberg
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Roberts
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
authors.forename: Christopher D M
authors.initials: CD
authors.lastname: Fletcher
authors.forename: Sandra
authors.initials: S
authors.lastname: Silberman
authors.forename: Sasa
authors.initials: S
authors.lastname: Dimitrijevic
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D016466:CHO Cells; D006224:Cricetinae; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005091:Exons; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000556:secondary; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D007124:Immunoenzyme Techniques; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use*; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000378:metabolism; D017154:Stromal Cells / Q000473:pathology; D015996:Survival Rate; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004273:DNA, Neoplasm; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha