Abstract 2581: Antitumor effect of Trametinib, a selective MEK inhibitor, in combination with 4-methylumbelliferone, a hyaluronic acid synthesis inhibitor, in Malignant pleural mesothelioma cell lines
Authors: Cho Hiroyuki , Matsumoto Seiji , Fujita Yoshiko , Kuroda Ayumi , Hashimoto Masaki , Takuwa Teruhisa , Menju Toshi , Sonobe Makoto , Kondo Nobuyuki , Date Hiroshi , Hasegawa Seiki 
Published: August 2015

Abstract
Introduction: Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy for which no targeted therapy exists. The mitogen-activated protein kinase (MAPK) pathway plays critical roles in the regulation of tumorigenesis in multiple solid tumors, including MPM. Trametinib, a selective MEK inhibitor, have a survival benefit in patients with V600 BRAF-mutant metastatic melanoma. The effect of trametinib on MPM cells has not been well studied. Hyaluronan (HA) is one of the major components of the extracellular matrix. MPM is in most cases associated with elevated amounts of HA, which has increased the malignant properties of MPM cells. The HA synthesis inhibitor 4-methylumbelliferone (4-MU) has antitumor effects in various malignant tumors, but its effect on MPM cells has not been well studied.
Purpose: We evaluated the effects of trametinib, 4-MU and their combination on MPM cells in vitro and in vivo.
Experimental Design: The effects of trametinib, 4-MU, and their combination on MPM cells were evaluated using cell viability assay, western blot analysis, and mouse xenograft model.
Results: Trametinib exhibited an antiproliferative activity in all four MPM cell lines, NCI-H226, NCI-H2452, NCI-H2052, and MSTO-211H, with IC50 values ranging from 0.15 μM to 12.7 μM. Trametinib blocked the phosphorylation of ERK until 72 hours and decreased the expression of CD44 in a dose-dependent manner. In addition, the expression of CD44 was inhibited (48-72 hours) after the suppression of ERK phosphorylation by trametinib. 4-MU exhibited an antiproliferative activity in MPM cells. 4-MU inhibited ERK phosphorylation but not CD44 expression. In mouse xenograft model, trametinib and 4-MU suppressed tumor growth (trametinib vs. control, P &lt; 0.0001; 4-MU vs. control, P &lt; 0.01), and their combination suppressed more strongly (combination vs. trametinib, P &lt; 0.01; combination vs. 4-MU, P &lt; 0.0001; combination vs. control, P &lt; 0.0001).
Conclusions: Trametinib and 4-MU exhibited antitumor activities in MPM cell lines. Furthermore, their combination exhibited more potent antitumor activities. These results suggests that Trametinib and 4-MU are promising therapeutic agents in MPM, and these combination therapies may be effective for the treatment of MPM.
Citation Format: Hiroyuki Cho, Seiji Matsumoto, Yoshiko Fujita, Ayumi Kuroda, Masaki Hashimoto, Teruhisa Takuwa, Toshi Menju, Makoto Sonobe, Nobuyuki Kondo, Hiroshi Date, Seiki Hasegawa. Antitumor effect of Trametinib, a selective MEK inhibitor, in combination with 4-methylumbelliferone, a hyaluronic acid synthesis inhibitor, in Malignant pleural mesothelioma cell lines. [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 2581. doi:10.1158/1538-7445.AM2015-2581