Trametinib plus 4-Methylumbelliferone Exhibits Antitumor Effects by ERK Blockade and CD44 Downregulation and Affects PD-1 and PD-L1 in Malignant Pleural Mesothelioma

J Thorac Oncol. 2017 Mar;12(3):477-490. doi: 10.1016/j.jtho.2016.10.023. Epub 2016 Nov 17.


Introduction: Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy in which the mitogen-activated protein kinase pathway plays a critical role in the regulation of tumorigenesis. Hyaluronic acid (HA) is a major component of the extracellular matrix, and elevated HA levels with a concurrent increase in malignant properties are associated with MPM.

Methods: We evaluated the effects of trametinib, a mitogen-activated protein kinase (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 by using cell viability assays, Western blot analysis, and a mouse xenograft model.

Results: Trametinib and 4-MU exhibited antiproliferative 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 [AP1] component), 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 with a control. The combination had a greater inhibitory effect than either monotherapy. Immunohistochemical analysis showed that trametinib treatment alone significantly reduced expression of programmed cell death 1 ligand 1. Furthermore, the combination of trametinib and 4-MU resulted in higher expression of programmed cell death 1 and programmed cell death 1 ligand 1 than did the 4-MU treatment alone.

Conclusions: Our results suggest that trametinib and 4-MU are promising therapeutic agents in MPM and that further study of the combination is warranted.

Keywords: 4-Methylumbelliferone; CD44; ERK; Malignant pleural mesothelioma; Trametinib.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • B7-H1 Antigen / metabolism*
  • Cell Proliferation / drug effects
  • Drug Therapy, Combination
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Hyaluronan Receptors / chemistry*
  • Hymecromone / pharmacology*
  • Indicators and Reagents / pharmacology
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mesothelioma / drug therapy*
  • Mesothelioma / metabolism
  • Mesothelioma / pathology
  • Mesothelioma, Malignant
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Pleural Neoplasms / drug therapy*
  • Pleural Neoplasms / metabolism
  • Pleural Neoplasms / pathology
  • Programmed Cell Death 1 Receptor / metabolism*
  • Pyridones / pharmacology*
  • Pyrimidinones / pharmacology*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • B7-H1 Antigen
  • CD274 protein, human
  • CD44 protein, human
  • Hyaluronan Receptors
  • Indicators and Reagents
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Pyridones
  • Pyrimidinones
  • trametinib
  • Hymecromone
  • Extracellular Signal-Regulated MAP Kinases