The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects

Hidekazu Itamura, Takero Shindo, Isao Tawara, Yasushi Kubota, Ryusho Kariya, Seiji Okada, Krishna V Komanduri, Shinya Kimura

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)e86331
JournalJCI insight
Volume1
Issue number10
StatePublished - Jul 7 2016

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Mitogen-Activated Protein Kinase Kinases
Graft vs Host Disease
T-Lymphocytes
Transplants
Neoplasms
trametinib
Hematopoietic Stem Cell Transplantation
Tacrolimus
Hematologic Neoplasms
Myeloid Cells
Antineoplastic Agents
Melanoma
B-Lymphocytes
Spleen
Phosphorylation
Pathology
Viruses
Skin
Survival
Liver

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Itamura, H., Shindo, T., Tawara, I., Kubota, Y., Kariya, R., Okada, S., ... Kimura, S. (2016). The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects. JCI insight, 1(10), e86331.

The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects. / Itamura, Hidekazu; Shindo, Takero; Tawara, Isao; Kubota, Yasushi; Kariya, Ryusho; Okada, Seiji; Komanduri, Krishna V; Kimura, Shinya.

In: JCI insight, Vol. 1, No. 10, 07.07.2016, p. e86331.

Research output: Contribution to journalArticle

Itamura, H, Shindo, T, Tawara, I, Kubota, Y, Kariya, R, Okada, S, Komanduri, KV & Kimura, S 2016, 'The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects', JCI insight, vol. 1, no. 10, pp. e86331.
Itamura H, Shindo T, Tawara I, Kubota Y, Kariya R, Okada S et al. The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects. JCI insight. 2016 Jul 7;1(10):e86331.
Itamura, Hidekazu ; Shindo, Takero ; Tawara, Isao ; Kubota, Yasushi ; Kariya, Ryusho ; Okada, Seiji ; Komanduri, Krishna V ; Kimura, Shinya. / The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects. In: JCI insight. 2016 ; Vol. 1, No. 10. pp. e86331.
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