title: Molecular analysis of secondary kinase mutations in imatinib-resistant gastrointestinal stromal tumors.
abstract: Most gastrointestinal stromal tumors (GISTs) are associated with activating kinase mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene, and imatinib has revolutionized the care of advanced GISTs. However, most patients gradually developed resistance to imatinib. We intend to identify the secondary kinase mutations in imatinib-resistant GISTs and to study the relationship between secondary kinase mutations and the clinical response to imatinib. Twelve advanced GIST patients, who have developed resistance to imatinib were included in this study. Paraffin-embedded pretreatment GIST specimens and progression lesions of the tumors after resistance to imatinib were analyzed for kinase mutations in exons 9, 11, 13, and 17 of KIT gene and exons of 10, 12, 14, and 18 of PDGFRA gene. Primary KIT mutations have been found in all but one of the primary tumors including one case harboring de novo double KIT exon 11 mutations. Secondary kinase mutations in KIT and PDGFRA were found in seven and 1 of 12 patients, respectively. Two patients harbored more than one secondary KIT mutations in different progression sites, and there are four types of clonal or polyclonal evolution being observed. The secondary PDGFRA exon 14 mutation H687Y is a novel mutation that has never been reported before. Acquired secondary kinase mutations are the most important cause of secondary imatinib resistance in advanced GISTs. The identification of secondary kinase mutations is important in the development of new therapeutic strategies.
authors.affiliation: Division of Hematology and Oncology, Mackay Memorial Hospital, 92, Section 2, Chungshan North Road, Taipei 10449, Taiwan.
authors.forename: Ken-Hong
authors.initials: KH
authors.lastname: Lim
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Huang
authors.forename: Li-Tzong
authors.initials: LT
authors.lastname: Chen
authors.forename: Tsang-En
authors.initials: TE
authors.lastname: Wang
authors.forename: Chien-Liang
authors.initials: CL
authors.lastname: Liu
authors.forename: Cheng-Shyong
authors.initials: CS
authors.lastname: Chang
authors.forename: Mei-Chin
authors.initials: MC
authors.lastname: Liu
authors.forename: Reuy-Kuen
authors.initials: RK
authors.lastname: Hsieh
authors.forename: Chin-Yuan
authors.initials: CY
authors.lastname: Tzen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha