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Updated: Jul 20, 2026
Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
Molecular correlates of imatinib resistance in gastrointestinal stromal tumors
Michael C Heinrich1, Christopher L Corless, Charles D Blanke
1Division of Hematology/Oncology, Department of Pathology, Oregon Health & Science University Cancer Institute, Oregon Health & Science University, Portland, OR, USA. Heinrich@ohsu.edu
Purpose:
Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT or platelet-derived growth factor alpha (PDGFRA) kinases, which are targets for imatinib. In clinical studies, 75% to 90% of patients with advanced GISTs experience clinical benefit from imatinib. However, imatinib resistance is an increasing clinical problem.
Patients And Methods:
One hundred forty-seven patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib. Specimens from pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. Secondary kinase mutations of KIT or PDGFRA that were identified in imatinib-resistant GISTs were biochemically profiled for imatinib sensitivity.
Results:
Molecular studies were performed using specimens from 10 patients with primary and 33 patients with secondary resistance. Imatinib-resistant tumors had levels of activated KIT that were similar to or greater than those typically found in untreated GISTs. Secondary kinase mutations were rare in GISTs with primary resistance but frequently found in GISTs with secondary resistance (10% v 67%; P = .002). Evidence for clonal evolution and/or polyclonal secondary kinase mutations was seen in three (18.8%) of 16 patients. Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical KIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on KIT kinase activity for activation of critical downstream signaling pathways.
Conclusion:
Different molecular mechanisms are responsible for primary and secondary imatinib resistance in GISTs. These findings have implications for future approaches to the growing problem of imatinib resistance in patients with advanced GISTs.
Insights
Gastrointestinal stromal tumor (GIST) patients can develop resistance to imatinib therapy. Secondary kinase mutations in KIT or PDGFRA are common in secondary imatinib resistance, impacting treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Gastrointestinal stromal tumors (GISTs) often harbor KIT or PDGFRA mutations.
- Imatinib is a targeted therapy for advanced GISTs, providing clinical benefit to most patients.
- Imatinib resistance is a significant challenge in managing advanced GISTs.
Purpose of the Study:
- To investigate the molecular mechanisms underlying imatinib resistance in GISTs.
- To identify molecular correlates of primary and secondary imatinib resistance.
- To assess the sensitivity of secondary kinase mutations to imatinib.
Main Methods:
- A randomized phase II clinical study of imatinib in 147 patients with advanced GISTs.
- Analysis of pretreatment and/or imatinib-resistant tumor specimens.
- Biochemical profiling of identified secondary KIT or PDGFRA kinase mutations for imatinib sensitivity.
Main Results:
- Secondary kinase mutations were infrequent in primary resistance but common in secondary resistance (67%).
- Clonal evolution and polyclonal secondary mutations were observed in some patients.
- Secondary mutations were associated with reduced imatinib sensitivity and nonrandom distribution.
- Imatinib-resistant GIST cells remain dependent on KIT kinase activity.
Conclusions:
- Distinct molecular mechanisms drive primary and secondary imatinib resistance in GISTs.
- Understanding these mechanisms is crucial for developing future therapeutic strategies.
- This research addresses the growing clinical problem of imatinib resistance in advanced GISTs.
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