Abstract B275: Dovitinib as a single-agent or in combination with other small molecule inhibitors for mutant BRAF melanomas.

Abstract

Abstract Background: Receptor tyrosine kinases (RTKs) modulate many oncogenic signaling pathways. RTKs can be activated as a result of feedback loops initiated from inhibition of downstream signaling components and contribute to resistance to small molecule targeted therapies. Target-specific inhibitors have provided many advances in cancer treatment, but it is becoming increasingly evident that single-agent treatment approaches are suboptimal. To address this, we performed single-agent compound screens against a panel of melanoma cell lines to select candidate agents for testing in combination agent screens (Cancer Discov 2013 3:52-67). One of the top single-agents effective in mutant BRAF melanomas was dovitinib (TKI258, CHIR258), a multi-RTK inhibitor shown to inhibit numerous type III, IV, and V RTKs. We present data examining the target profile of dovitinib in short-term cultured melanoma cell lines and describe effective partner agents for further testing as combination therapies. Materials and Methods: Twenty-five melanoma cell lines were screened against 150 agents. The most efficacious forty agents from the single-agent screen were collated and three consensus concentrations were determined for each compound to perform pair-wise combinations (Cancer Discov 2013 3:52-67). Growth inhibition was evaluated by ATP luminescent detection by CellTiterGlo®. Colony formation experiments were performed to confirm positive drug interactions. Phosphoproteomic approaches were used to further evaluate targets of dovitinib. Results: Dovitinib was one of the top hits from this single-agent screen that was effective in mutant BRAF melanoma cell lines. Dovitinib does not inhibit mutant BRAF directly, but inhibits RTKs. We found that multiple RTK targets of dovitinib are expressed and active in mutant BRAF melanoma cell lines. Furthermore, we found that dovitinib combines well with vemurafenib and MEK and AKT inhibitors to inhibit colony formation ability and cell proliferation. This was seen in both vemurafenib-sensitive and resistant cell lines. Conclusions: These findings further demonstrate the utility of using both single- and combination agent screening to determine genotype specific compound effects. Furthermore, these results support the rationale for using dovitinib as a partner agent with several small molecule inhibitors for melanoma combination therapy, especially in the vemurafenib-resistant setting. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B275. Citation Format: Casey G. Langdon, Matthew A. Held, Andrew B. Koo, Michael Klein, Zongzhi Liu, James T. Platt, David F. Stern. Dovitinib as a single-agent or in combination with other small molecule inhibitors for mutant BRAF melanomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B275.