Abstract 2028: Co-targeting histone deacetylases and oncogenic BRAF synergistically kills human melanoma cell by caspase-independent cell death.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Inherent and acquired resistance of melanomas carrying active mutations in BRAF to mutant BRAF inhibitors (BRAFi) remains a major obstacle for curative treatment of the disease. Since both BRAFi and histone deacetylase inhibitors (HDACi) kill sensitive melanoma cells by activating the BH3-only protein Bim, we examined whether they cooperate in killing of BRAF(V600E) melanoma cells. We show here that co-treatment with the HDACi SAHA and the BRAFi PLX4720 synergistically kills BRAF(V600E) melanoma cells in vitro, and that the combination of SAHA and the clinically available BRAFi vemurafenib cooperatively inhibits melanoma growth in vivo. Although SAHA plus PLX4720 activated the caspase cascade, the latter did not appear to be indispensable for induction of cell death. Likewise, PLX4720 alone kills sensitive melanoma cells in a caspase-independent manner. Similar to caspases, Bim seemed dispensable for synergistic killing by SAHA and PLX4720. The mechanism by which co-treatment with HDACi and BRAFi kills BRAFV600E melanoma cells remains to be elucidated, but we have found that this is not mediated by receptor-interacting protein 1 (RIP1), which is essential for induction of programmed necrosis. Regardless, our results suggest that combinations of HDACi and BRAFi may have therapeutic advantages, in that the conventional caspase-dependent, mitochondrial-mediated apoptotic machinery is often suppressed in melanoma cells. Citation Format: Su Tang Guo, Fritz Lai, Chen Chen Jiang, Chun Yan Wang, Margaret Farrelly, Hsin-Yi Tseng, Meng Na Chi, Lei Jin, Peter Hersey, Xu Dong Zhang. Co-targeting histone deacetylases and oncogenic BRAF synergistically kills human melanoma cell by caspase-independent cell death. [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 2028. doi:10.1158/1538-7445.AM2013-2028