Abstract 775: Anti-tumor effects of dovitinib, a multi-target kinase inhibitor, in patient-derived gastrointestinal stromal tumor (GIST) xenograft models

Abstract

Abstract Background: The majority of GISTs are driven by KIT/PDGFRA gain of function mutations. Advanced GIST is routinely treated with tyrosine kinase inhibitors (TKI; e.g imatinib, sunitinib and regorafenib). However, with time, heterogeneous resistance to these agents occurs, mainly due to acquired mutations in KIT. We tested the efficacy of dovitinib, which acts against VEGFR, FGFR, FLT3, PDGFRB and KIT, using patient-derived GIST xenograft models. Methods: NMRI nu/nu mice (n = 47) were bilaterally transplanted with the human GIST xenografts: a dose-dependent-imatinib-sensitive model UZLX-GIST2 (KIT: p.A502_Y503dup) or a model resistant to both imatinib and sunitinib, UZLX-GIST9 (KIT: p.P577del+p.W557LfsX5+p.D820G). Mice were divided to four treatment groups: control (untreated), imatinib (50 mg/kg/bid p.o.), imatinib (100 mg/kg/bid p.o.) and dovitinib (30 mg/kg/qd p.o.). Efficacy was assessed by tumor volume measurement (3x/week), histopathology [hematoxylin & eosin staining (H&E)], immunohistochemistry [Ki67, phospho-Histone H3 (pHH3), cleaved PARP] and Western blotting analysis of KIT signaling. Histologic response (HR) was graded as previously described1. Microvascular density (MVD) was assessed by counting CD31 positive vessels. Mann Whitney U test was used for statistical analysis. Results: After three weeks of treatment, dovitinib caused tumor volume reduction (to 37%) in UZLX-GIST2 and disease stabilization in UZLX-GIST9. Only minimal HR was observed in imatinib-treated cohorts, whereas dovitinib induced grade 2-3 HR in >50% of tumors in both models. Compared to control, dovitinib reduced mitotic activity by 22.6 fold (p<0.0001) in UZLX-GIST2, whereas no significant difference was observed in UZLX-GIST9 model. Results were confirmed by pHH3 and Ki67 immunostainings. Apoptotic activity was decreased in dovitinib treated UZLX-GIST2 tumors compared to control. MVD was reduced both in UZLX-GIST2 (1.6 fold; p<0.05) and in UZLX-GIST9 (1.3 fold; p = 0.059) under dovitinib treatment. Furthermore, it partially inhibited KIT, AKT and 4EBP-1 activation in UZLX-GIST2. Conclusion: The multi-kinase inhibitor dovitinib showed anti-tumor efficacy in GIST xenograft models, though the effect was more pronounced in KIT exon 9 mutant (UZLX-GIST2). The decrease in MVD in both models suggested that the anti-tumor effect in these models was at least partially mediated by an anti-angiogenic effect of dovitinib. 1 Antonescu et al. Clin Cancer Res. 2005; 11:4182-90 Citation Format: Yemarshet Kelemework Gebreyohannes, Thomas Van Looy, Agnieszka Wozniak, Jasmien Wellens, Haifu Li, Jasmien Cornillie, Ulla Vanleeuw, Lise Vreys, Matthew Squires, Ana-Maria Rodringuez, Maria Debiec-Rychter, Raf Sciot, Patrick Schöffski. Anti-tumor effects of dovitinib, a multi-target kinase inhibitor, in patient-derived gastrointestinal stromal tumor (GIST) xenograft models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 775. doi:10.1158/1538-7445.AM2015-775