Molecular analysis of secondary kinase mutations in imatinib-resistant gastrointestinal stromal tumors
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
DOI:
10.1007/s12032-007-9014-2
Publication Date:
2007-10-05T20:03:10Z
AUTHORS (9)
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.
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CITATIONS (38)
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