A Panel of Gastrointestinal Stromal Tumours (gist) Xenograft Models for in Vivo Preclinical Drug Testing

ABSTRACT Aim: Most GIST are dependent on the KIT/PDGFRA signalling pathway and therefore can be treated with specific tyrosine kinase inhibitors (TKI). With time GIST develop resistance to the TKI. We need reliable models which can be used for preclinical drug testing. Methods: Patient-derived xenografts were established in nu/nu NMRI mice by subcutaneous implantation of fresh, surgically resected tumour specimens from consenting patients with GIST treated at the University Hospitals Leuven. Once tumour growth was observed, pieces of tumour were re-transplanted to next generations of mice. At each passage tumour fragments were collected for histological and molecular characterization. A model was considered to be established after observing stable histological and molecular features for at least two passages. Results: At present we have access to five successfully established GIST models, with different KIT mutations and different sensitivity to standard TKIs (Table). Established GIST xenograft models and their sensitivity to standard treatment. In vivo efficacy was assessed by % of relative tumour volume after 3 weeks under either imatinib (50mg/kg BID) or sunitinib (40mg/kg QD) Model* KIT mutation In vivo efficacy Imatinib Sunitinib UZLX-GIST1 p.V560D 20 20 UZLX-GIST2 p.A502_Y503dup 170 80 UZLX-GIST3 p.W557_V559delinsF 25 25 UZLX-GIST4 p.K558_G565delinsR 45 20 UZLX-GIST9 p.P577del; p.W557LfsX5; p.D820G 250 170 *models which showed tumor growth for at least two passages Untreated tumours from subsequent passages show morphological and immunohistochemical features resembling the original patient biopsy, verifying the stability GIST xenografts growth. KIT mutational status has also been confirmed in samples obtained from all models. These models are used for subsequent testing of new therapeutic approaches and current results have had an impact on at least four prospective clinical trials. If needed, we parallel our patient-derived models with in vitro or in vivo studies using one of the few established GIST cell lines. Conclusions: Our established GIST xenografts maintain the histological and molecular characteristics of the original patient sample and are a very useful and reliable preclinical platform for testing the new targeted approaches in GIST. Disclosure: All authors have declared no conflicts of interest.