Characterization and assessment of the sensitivity and resistance of a newly established human gastrointestinal stromal tumour xenograft model to treatment with tyrosine kinase inhibitors
| Autor: | Thomas Van Looy, Raf Sciot, Jasmien Cornillie, Haifu Li, Giuseppe Floris, Maria Debiec-Rychter, Patrick Schöffski, Yemarshet K. Gebreyohannes, Jasmien Wellens, Agnieszka Wozniak, Ulla Vanleeuw |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Pathology
medicine.medical_specialty Gastrointestinal stromal tumour medicine.drug_class Resistance Tyrosine kinase inhibitor PDGFRA Tyrosine-kinase inhibitor chemistry.chemical_compound Regorafenib Sunitinib medicine neoplasms biology GiST CD117 business.industry Research Xenograft Imatinib digestive system diseases Oncology chemistry biology.protein Cancer research business Tyrosine kinase medicine.drug |
| Zdroj: | Clinical Sarcoma Research |
| Popis: | Background Acquired resistance to tyrosine kinase inhibitors (TKIs) in gastrointestinal stromal tumours (GISTs) is most commonly caused by secondary KIT or PDGFRA mutations. In this study we characterize a newly established GIST xenograft model, UZLX-GIST9, and evaluate the in vivo response of the model to standard TKIs (imatinib, sunitinib, and regorafenib). Methods Tumour fragments from a metastatic lesion of a GIST patient clinically progressing after treatment with imatinib, sunitinib and regorafenib were engrafted in a nude, immunodeficient mouse. Upon sequential passaging from mouse to mouse, tumour fragments were collected for histopathological and molecular characterization. The sensitivity of the model to treatment with TKIs was evaluated in 28 mice [passage 2 (n = 8), passage 4 (n = 20), 41 tumours]. Mice were grouped as follows: control (untreated), imatinib (50 mg/kg/BID), imatinib (100 mg/kg/BID), sunitinib (40 mg/kg/QD), and regorafenib (30 mg/kg/QD). After three weeks of oral treatment, tumours were collected for subsequent analysis. The efficacy of treatment was assessed by tumour volume, histopathology and Western immunoblotting. Results UZLX-GIST9 maintains the same typical morphological features and immunohistochemical characteristics as the original patient biopsy and expresses CD117 and DOG1. The KIT mutational profile (p.P577del + W557LfsX5+ D820G) remains the same as the original tissue sample originating from an intraspinal metastatic site. Three week treatment with different TKIs showed that the model is resistant to imatinib. Sunitinib induces tumour growth delay and regorafenib reduces the tumour burden by 30% as compared to control animals. While none of the TKIs had a significant effect on cell proliferation or cell survival, a remarkable increase of necrosis and significant reduction of microvessel density was observed under sunitinib and regorafenib. Western immunoblotting showed a mild reduction in KIT and AKT activation only in regorafenib treated tumours. Conclusions We established a novel human GIST xenograft, UZLX-GIST9, harbouring KIT exon 11 and 17 mutations and maintaining the pheno-and genotype of the original tumour. UZLX-GIST9 shows different levels of response to standard TKIs. This model will help to study TKI resistance and to explore novel treatment approaches for patients with TKI-resistant GIST. |
| Databáze: | OpenAIRE |
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