Abstract 1620: Dovitinib has anti-tumor activity in gastrointestinal stromal tumor (GIST) cell lines.
Authors: Growney Joseph D. , Li Fang , Qiu Shumei , Gorbatcheva Bella , Battalagine Linda , Mestan Juergen , Manley Paul , Squires Matthew , Cao Alex , Monahan John E. 
Published: August 2014

Background: Gastrointestinal stromal tumors (GISTs) are the most common gastrointestinal tract sarcoma, with 5000-6000 cases per year diagnosed in the United States. Most GISTs carry activating mutations in KIT (≈ 75% of cases) or PDGFR alpha (10%-15%). Imatinib, a KIT/PDGFR inhibitor, is the frontline treatment for GIST, although secondary mutations commonly lead to acquired resistance. Dovitinib inhibits several kinase targets important in the development and maintenance of GISTs, including KIT, PDGFR, VEGFR, and FGFR. This study was designed to evaluate the single-agent activities of imatinib and dovitinib in a panel of GIST cell lines and an imatinib-sensitive mouse model.

Methods: In vitro sensitivity was examined in both imatinib-sensitive (GIST-T1 and GIST882) and -insensitive (GIST430 and GIST48) cell lines. KIT phosphorylation was measured by Western blot and sandwich ELISA. Imatinib and dovitinib monotherapy were evaluated for tumor growth inhibition and delay in a nu/nu mouse xenograft model using GIST-T1 xenografts. Dovitinib was administered by mouth at either 60 mg/kg daily for 14 days or 30 mg/kg daily for 21 days. Imatinib was given at 100 mg/kg by mouth twice daily. Following treatment, dosing was terminated, and tumors were allowed to regrow off treatment. Kaplan-Meier analysis was used to determine tumor growth delay, reported as median time to reach endpoint (tumor volume ≥ 1000 mm3).

Results: Imatinib and dovitinib inhibit KIT phosphorylation in GIST-T1,

GIST882, GIST430 and GIST48 cells, although imatinib appeared to be more potent. Dovitinib and imatinib both potently inhibited the proliferation, GI50 10-100 nM, of imatinib-sensitive GIST-T1 and GIST882 cell lines; GI50 was &gt; 500 nM in imatinib-insensitive GIST48 and GIST430 cell lines. In vivo, imatinib and dovitinib were well tolerated for 14- and 21-day treatment cycles. In the 14-day treatment model, imatinib and dovitinib led to 52% and 59% tumor regression, respectively, and median time to regrowth was 69 days for both agents compared with 31 days for vehicle. In the 21-day treatment model, imatinib and dovitinib led to 66% and 36% tumor regression, respectively, and median time to regrowth was 81 and 69 days, respectively, compared with 27 days for vehicle.

Conclusions: Dovitinib inhibits KIT signaling and has similar growth-inhibition activity to imatinib in imatinib-sensitive GIST cell lines. In xenograft models, both imatinib and dovitinib are well tolerated, induce tumor regression, and delay tumor regrowth. The additional kinase inhibitory activities of dovitinib offer the possibility for enhanced or differentiated activity to imatinib in certain settings. Experiments are ongoing to explore this possibility. These data suggest that dovitinib may have therapeutic benefit in GIST, with efficacy resulting from a combination of the inhibition of KIT and other kinases.

Citation Format: Joseph D. Growney, Fang Li, Shumei Qiu, Bella Gorbatcheva, Linda Battalagine, Juergen Mestan, Paul Manley, Matthew Squires, Alex Cao, John E. Monahan. Dovitinib has anti-tumor activity in gastrointestinal stromal tumor (GIST) cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1620. doi:10.1158/1538-7445.AM2013-1620