Molecular analysis of secondary kinase mutations in imatinib-resistant gastrointestinal stromal tumors

• DOI: 10.1007/s12032-007-9014-2
• Publication Date: 2007-10-05T20:03:10Z
• Authors: Ken-Hong Lim; Ming-Jer Huang; Li-Tzong Chen; Tsang-En Wang; Chien-Liang Liu; Cheng-Shyong Chang; Mei-Chin Liu; Reuy-Kuen Hsieh; Chin-Yuan Tzen
• Keywords: Aged, 80 and over; Male; 0301 basic medicine; Receptor, Platelet-Derived Growth Factor alpha; Gastrointestinal Stromal Tumors; Antineoplastic Agents; Middle Aged; Piperazines; 3. Good health; Proto-Oncogene Proteins c-kit; 03 medical and health sciences; Pyrimidines; 0302 clinical medicine; Drug Resistance, Neoplasm; Benzamides; Mutation; Imatinib Mesylate; Humans; Female; Protein Kinase Inhibitors; Aged

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.