The Exportin-1 Inhibitor Selinexor Exerts Superior Antitumor Activity when Combined with T-Cell Checkpoint Inhibitors.
Selinexor, a selective inhibitor of nuclear export (SINE) compound targeting exportin-1, has previously been shown to inhibit melanoma cell growthin vivoWe hypothesized that combining selinexor with antibodies that block or disrupt T-cell checkpoint molecule signaling would exert superior antimelanoma activity.In vitro, selinexor increasedPDCD1andCTLA4gene expression in leukocytes and inducedCD274gene 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.
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
Matthew R
MR
Farren
Department of Molecular Genetics, The Ohio State University, Columbus, Ohio.|Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio.
Rebecca C
RC
Hennessey
Target Validation Shared Resource, The Ohio State University, Columbus, Ohio.
Reena
R
Shakya
Division of Internal Medicine, The Ohio State University, Columbus, Ohio.
Omar
O
Elnaggar
Center for Biostatistics, The Ohio State University, Columbus, Ohio.
Gregory
G
Young
Division of Internal Medicine, The Ohio State University, Columbus, Ohio.
Kari
K
Kendra
Karyopharm Therapeutics, Newton, Massachusetts.
Yosef
Y
Landesman
Karyopharm Therapeutics, Newton, Massachusetts.
Sivan
S
Elloul
Karyopharm Therapeutics, Newton, Massachusetts.
Marsha
M
Crochiere
Karyopharm Therapeutics, Newton, Massachusetts.
Boris
B
Klebanov
Karyopharm Therapeutics, Newton, Massachusetts.
Trinayan
T
Kashyap
Department of Molecular Genetics, The Ohio State University, Columbus, Ohio.|Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio.
Christin E
CE
Burd
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia. gregory.b.lesinski@emory.edu.
Gregory B
GB
Lesinski
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D056747:Immunomodulation / Q000187:drug effects; D028884:Karyopherins / Q000037:antagonists & inhibitors*; D008546:Melanoma, Experimental; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology*; D000097606:Exportin 1 Protein
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; D006834:Hydrazines; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D000097606:Exportin 1 Protein; C556706:CTLA4 protein, human; C585161:selinexor