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Mol Cancer Ther. 2017 Mar;16(3):417-427. doi: 10.1158/1535-7163.MCT-16-0498. Epub 2017 Feb 1.

The Exportin-1 Inhibitor Selinexor Exerts Superior Antitumor Activity when Combined with T-Cell Checkpoint Inhibitors.

Author information

1
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
2
Department of Molecular Genetics, The Ohio State University, Columbus, Ohio.
3
Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio.
4
Target Validation Shared Resource, The Ohio State University, Columbus, Ohio.
5
Division of Internal Medicine, The Ohio State University, Columbus, Ohio.
6
Center for Biostatistics, The Ohio State University, Columbus, Ohio.
7
Karyopharm Therapeutics, Newton, Massachusetts.
8
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia. gregory.b.lesinski@emory.edu.

Abstract

Selinexor, a selective inhibitor of nuclear export (SINE) compound targeting exportin-1, has previously been shown to inhibit melanoma cell growth in vivo We hypothesized that combining selinexor with antibodies that block or disrupt T-cell checkpoint molecule signaling would exert superior antimelanoma activity. In vitro, selinexor increased PDCD1 and CTLA4 gene expression in leukocytes and induced CD274 gene expression in human melanoma cell lines. Mice bearing syngeneic B16F10 melanoma tumors demonstrated a significant reduction in tumor growth rate in response to the combination of selinexor and anti-PD-1 or anti-PD-L1 antibodies (P < 0.05). Similar results were obtained in B16F10-bearing mice treated with selinexor combined with anti-CTLA4 antibody. Immunophenotypic analysis of splenocytes by flow cytometry revealed that selinexor alone or in combination with anti-PD-L1 antibody significantly increased the frequency of both natural killer cells (P ≤ 0.050) and CD4+ T cells with a Th1 phenotype (P ≤ 0.050). Further experiments indicated that the antitumor effect of selinexor in combination with anti-PD-1 therapy persisted under an alternative dosing schedule but was lost when selinexor was administered daily. These data indicate that the efficacy of selinexor against melanoma may be enhanced by disrupting immune checkpoint activity. Mol Cancer Ther; 16(3); 417-27. ©2017 AACRSee related article by Tyler et al., p. 428.

PMID:
28148715
PMCID:
PMC5407496
DOI:
10.1158/1535-7163.MCT-16-0498
[Indexed for MEDLINE]
Free PMC Article

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