title: The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects.
abstract: The efficacy of allogeneic hematopoietic stem cell transplantation for hematologic malignancies is limited by the difficulty in suppressing graft-versus-host disease (GVHD) without compromising graft-versus-tumor (GVT) effects. We previously showed that RAS/MEK/ERK signaling depends on memory differentiation in human T cells, which confers susceptibility to selective inhibition of naive T cells. Actually, antineoplastic MEK inhibitors selectively suppress alloreactive T cells, sparing virus-specific T cells in vitro. Here, we show that trametinib, a MEK inhibitor clinically approved for melanoma, suppresses GVHD safely without affecting GVT effects in vivo. Trametinib prolonged survival of GVHD mice and attenuated GVHD symptoms and pathology in the gut and skin. It inhibited ERK1/2 phosphorylation and expansion of donor T cells, sparing Tregs and B cells. Although high-dose trametinib inhibited myeloid cell engraftment, low-dose trametinib suppressed GVHD without severe adverse events. Notably, trametinib facilitated the survival of mice transplanted with allogeneic T cells and P815 tumor cells with no residual P815 cells observed in the livers and spleens, whereas tacrolimus resulted in P815 expansion. These results confirm that trametinib selectively suppresses GVHD-inducing T cells while sparing antitumor T cells in vivo, which makes it a promising candidate for translational studies aimed at preventing or treating GVHD.
authors.affiliation: Department of Hematology, Respiratory Medicine and Oncology, Saga University School of Medicine, Saga, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Itamura
authors.affiliation: Department of Hematology, Respiratory Medicine and Oncology, Saga University School of Medicine, Saga, Japan.
authors.forename: Takero
authors.initials: T
authors.lastname: Shindo
authors.affiliation: Department of Hematology/Oncology, Mie University School of Medicine, Tsu, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Tawara
authors.affiliation: Department of Hematology, Respiratory Medicine and Oncology, Saga University School of Medicine, Saga, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kubota
authors.affiliation: Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Ryusho
authors.initials: R
authors.lastname: Kariya
authors.affiliation: Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Okada
authors.affiliation: Adult Stem Cell Transplant Program and Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Krishna V
authors.initials: KV
authors.lastname: Komanduri
authors.affiliation: Department of Hematology, Respiratory Medicine and Oncology, Saga University School of Medicine, Saga, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
mesh_terms: D000818:Animals; D006086:Graft vs Host Disease / Q000188:drug therapy*; D020350:Graft vs Tumor Effect; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib