Abstract 795: Dovitinib exerts potent antitumor effects in gastrointestinal stromal tumors

Abstract Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumours of the gastrointestinal (GI) tract. Although Imatinib is the current first-line therapy for patients not suitable for surgical resection, 10 - 20% of GIST patients taking Imatinib do not respond to this therapy and 40-50% of the patients develop acquired resistance to Imatinib following partial response or stable disease. Thus, novel treatments are needed for GIST. In the present study, four different patient-derived xenograft (PDX) GIST models were used to demonstrate that Imatinib effectively caused tumor regression in GIST26-0208A and GIST09-0210 models with the common exon 11 KIT W557-K558 mutation (Imatinib-sensitive models), inhibited tumor growth of GIST27-0510 model with Y568-I571 and P573-L576 deletion and delayed tumor growth in GIST27-0612 with wild-type KIT. Unlike Imatinib, Dovitinib effectively caused tumor regression in all four PDX models tested regardless of their KIT mutational status. On GIST27-0510 model, tumor regression was observed as early as day 3 of Dovitinib treatment and continued to approximately 22% of the initial tumor volume. Dovitinib provided longer progression-free period than Imatinib after a 21-day treatment cycle. In the GIST26-0208A model, signs of tumor regrowth were observed on day 2 for Imatinib and day 59 for Dovitinib following a 21-day treatment. Dovitinib treatment took approximately 3.7 - 5 times longer to reach initial tumor volume than Imatinib following a 21-day treatment. Utilizing micro-Positron Emission Tomography (mPET), both Imatinib and Dovitinib treatment showed decreased SUV and TLG readings after 8-day treatment in GIST26-0208A. A trend of increasing activity was observed in Imatinib but not in Dovitinib-treated tumors at day 11 and day 21 following an 8-day treatment, suggesting mPET could potentially be used to access tumor response to Dovitinib. In Imatinib/Dovitinib-sensitive models, Imatinib and Dovitinib induced significant reduction in expression of p-ERK1/2, Bim, p-AKT (Ser473) and p-Cdc2 at 72 hours post treatment. Although inhibition of p-c-Kit (Tyr568/570) was observed, higher levels of p-Histone H2A-X (Ser139) and Cleaved PARP expression were observed in Dovitinib than Imatinib treatment, suggesting that Dovitinib was more effective than Imatinib in inducing cell death. Our data showed that Dovitinib treatment is able to provide greater advantages over Imatinib in all four PDX models regardless of their KIT mutational status, suggesting that Dovitinib may offer an alternative treatment for GIST that are insensitive to Imatinib. Citation Format: Huynh T. Hung, Richard Ong, Pierce Chow. Dovitinib exerts potent antitumor effects in gastrointestinal stromal tumors. [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 795. doi:10.1158/1538-7445.AM2015-795