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Updated: Jul 5, 2026
Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
Molecular analysis of secondary kinase mutations in imatinib-resistant gastrointestinal stromal tumors
Ken-Hong Lim1, Ming-Jer Huang, Li-Tzong Chen
1Division of Hematology and Oncology, Mackay Memorial Hospital, 92, Section 2, Chungshan North Road, Taipei 10449, Taiwan.
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.
Insights
Acquired secondary kinase mutations in KIT and PDGFRA genes are the primary cause of imatinib resistance in advanced gastrointestinal stromal tumors (GISTs). Identifying these mutations is crucial for developing new GIST treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gastrointestinal stromal tumors (GISTs) often harbor KIT or PDGFRA gene mutations.
- Imatinib therapy significantly improved outcomes for advanced GISTs.
- Acquired resistance to imatinib is a major clinical challenge.
Purpose of the Study:
- To identify secondary kinase mutations in imatinib-resistant GISTs.
- To investigate the link between secondary mutations and imatinib response.
- To understand the evolution of resistance mechanisms.
Main Methods:
- Analysis of kinase mutations in KIT and PDGFRA genes (exons 9, 11, 13, 17 for KIT; 10, 12, 14, 18 for PDGFRA).
- Study included 12 advanced GIST patients resistant to imatinib.
- Comparison of mutations in pretreatment specimens and post-resistance progression lesions.
Main Results:
- Primary KIT mutations were prevalent in most GISTs.
- Secondary KIT mutations were found in 7 out of 12 patients.
- A novel PDGFRA exon 14 mutation (H687Y) was identified in one patient.
- Clonal evolution with multiple secondary mutations was observed in some cases.
Conclusions:
- Acquired secondary kinase mutations are the main drivers of imatinib resistance in advanced GISTs.
- Identifying these secondary mutations is vital for future therapeutic development.
- Understanding resistance mechanisms can guide the design of novel treatment strategies for GIST.
