Trametinib plus 4-methylumbelliferone exhibits antitumor effects by ERK blockade and CD44 downregulation and affects PD1 and PD-L1 in malignant pleural mesothelioma

Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer 2016 November 17 [Epub ahead of print] [Link]

Cho H, Matsumoto S, Fujita Y, Kuroda A, Menju T, Sonobe M, Kondo N, Torii I, Nakano T, Lara PN, Gandara DR, Date H, Hasegawa S


Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy in which the mitogen-activated protein kinase (MAPK) pathway plays a critical role in the regulation of tumorigenesis. Hyaluronan (HA) is a major component of the extracellular matrix, and elevated HA levels, with a concurrent increase in malignant properties, are associated with MPM.
We evaluated the effects of trametinib, a MAPK kinase enzyme (MEK) inhibitor, and 4-methylumbelliferone (4-MU), an HA synthesis inhibitor, alone and in combination on MPM cells in vitro and in vivo. We studied the effects of trametinib, 4-MU, and their combination on MPM cells using cell viability assays, western blot analysis, and a mouse xenograft model.
Trametinib and 4-MU exhibited anti-proliferative activity in MPM cells. Trametinib blocked MEK-dependent extracellular signal-regulated kinase (ERK) phosphorylation and decreased CD44 expression in a concentration-dependent manner. Trametinib inhibited the expression of Fra-1, the activator protein-1 (AP-1) component, and inhibited ERK phosphorylation and decreased CD44 expression. 4-MU inhibited ERK phosphorylation, but not CD44 expression. In a mouse xenograft model, trametinib and 4-MU alone suppressed tumor growth compared to a control. The combination had a greater inhibitory effect than either monotherapy. Immunohistochemical analysis showed that trametinib treatment alone significantly reduced PD-L1 expression. Furthermore, the combination of trametinib and 4-MU resulted in higher expression of PD1 and PD-L1 than did the 4-MU treatment alone.
Our results suggest that trametinib and 4-MU are promising therapeutic agents in MPM and that further study of the combination is warranted.