Related Experiment Video
Updated: May 13, 2026
Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
Intermittent and continuous imatinib in a human GIST xenograft model carrying KIT exon 17 resistance mutation D816H
Mona-Elisabeth Revheim1, Alexandr Kristian, Eirik Malinen
1Department of Radiology and Nuclear Medicine, Oslo University Hospital, Nydalen, Oslo, Norway. mona.elisabeth.revheim@ous-hf.no
Background:
Acquired resistance to imatinib is frequently caused by secondary KIT mutations. We have investigated the effects of imatinib in mice with human gastrointestinal stromal tumour (GIST) xenograft which harbours a primary exon 11 deletion mutation and a secondary imatinib resistance mutation D816H in exon 17. Such mutations are commonly present in imatinib-resistant GIST in humans.
Material And Methods:
The mice were randomly allocated to receive imatinib either continuously or intermittently. Dynamic (18)F-FDG PET was performed and blood volume fraction (vB), rate transfer constants (k1, k2, k3) and metabolic rate of (18)F-FDG (MRFDG) were computed using a three-compartment model. Tumours were evaluated for the mitotic rate and the expression of HIF-1α , caspase-3 and glucose transporters (GLUTs).
Results:
Both intermittent and continuous imatinib delayed tumour growth significantly compared to controls, significantly in favour of the latter. k1 (representing perfusion, vascular permeability and binding of (18)F-FDG to the GLUTs) was significantly higher in the intermittent group compared to the continuous group, as was tumour GLUT-3 expression. k3 (representing internalisation of (18)F-FDG to the cells) and MR(FDG) were significantly lower.
Conclusion:
Imatinib delays GIST xenograft growth despite the presence of the D816H resistance mutation. The schedule of imatinib administration may influence tumour glucose uptake rate and metabolic rate.
Insights
Imatinib treatment delays gastrointestinal stromal tumour (GIST) growth in mice, even with resistance mutations. Intermittent dosing affects tumour glucose metabolism differently than continuous dosing.
Area of Science:
- Oncology
- Pharmacology
- Medical Imaging
Background:
- Acquired resistance to imatinib in gastrointestinal stromal tumours (GIST) is often due to secondary KIT mutations.
- This study examines imatinib efficacy in a GIST xenograft model with both primary exon 11 deletion and secondary D816H exon 17 resistance mutations.
Purpose of the Study:
- To investigate the effects of continuous versus intermittent imatinib administration on GIST xenografts harboring imatinib resistance mutations.
- To evaluate the impact of different imatinib dosing schedules on tumor glucose metabolism using dynamic (18)F-FDG PET imaging.
Main Methods:
- Mice with GIST xenografts were randomized to receive continuous or intermittent imatinib.
- Dynamic (18)F-FDG PET scans were analyzed using a three-compartment model to compute kinetic parameters (k1, k2, k3) and metabolic rate (MRFDG).
- Tumor mitotic rate and expression of HIF-1α, caspase-3, and glucose transporters (GLUTs) were assessed.
Main Results:
- Both imatinib schedules significantly delayed tumor growth compared to controls, with continuous dosing showing a greater effect.
- Intermittent dosing led to higher k1 (perfusion, permeability, (18)F-FDG binding) and GLUT-3 expression.
- Tumor internalisation rate (k3) and metabolic rate of (18)F-FDG (MRFDG) were lower in the intermittent group.
Conclusions:
- Imatinib demonstrates efficacy in delaying GIST xenograft growth, even in the presence of the D816H resistance mutation.
- The dosing schedule of imatinib may significantly influence tumor glucose uptake and metabolic activity.
