Intermittent and continuous imatinib in a human GIST xenograft model carrying KIT exon 17 resistance mutation D816H

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 (v (B)), rate transfer constants (k (1), k (2), k (3)) and metabolic rate of (18)F-FDG (MR (FDG)) 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. k (1) (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. k (3) (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.