title: Trametinib plus 4-Methylumbelliferone Exhibits Antitumor Effects by ERK Blockade and CD44 Downregulation and Affects PD-1 and PD-L1 in Malignant Pleural Mesothelioma.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Our results suggest that trametinib and 4-MU are promising therapeutic agents in MPM and that further study of the combination is warranted.
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Thoracic Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Thoracic Surgery, Hyogo College of Medicine, Nishinomiya, Japan. Electronic address: smatumo@hyo-med.ac.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Department of Thoracic Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Department of Thoracic Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kuroda
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Toshi
authors.initials: T
authors.lastname: Menju
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sonobe
authors.affiliation: Department of Thoracic Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kondo
authors.affiliation: Department of Pathology, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Torii
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Division of Hematology and Oncology, University of California Davis, Sacramento, CA.
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
authors.affiliation: Division of Hematology and Oncology, University of California Davis, Sacramento, CA.
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
authors.affiliation: Department of Thoracic Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Seiki
authors.initials: S
authors.lastname: Hasegawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D060890:B7-H1 Antigen / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004359:Drug Therapy, Combination; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry*; D006923:Hymecromone / Q000494:pharmacology*; D007202:Indicators and Reagents / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D007202:Indicators and Reagents; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D006923:Hymecromone; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: 4-Methylumbelliferone; CD44; ERK; Malignant pleural mesothelioma; Trametinib