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Leukemia. 2016 Jan;30(1):190-9. doi: 10.1038/leu.2015.194. Epub 2015 Jul 23.

Activity of a selective inhibitor of nuclear export, selinexor (KPT-330), against AML-initiating cells engrafted into immunosuppressed NSG mice.

Author information

1
Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
2
Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA.
4
Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
5
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
6
Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
7
Department of Haematology, UCL Cancer Institute, University College London, London, UK.
8
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
9
Karyopharm Therapeutics, Natick, MA, USA.
10
Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Medical Center, New York, NY, USA.

Abstract

Currently available combination chemotherapy for acute myeloid leukemia (AML) often fails to result in long-term remissions, emphasizing the need for novel therapeutic strategies. We reasoned that targeted inhibition of a prominent nuclear exporter, XPO1/CRM1, could eradicate self-renewing leukemia-initiating cells (LICs) whose survival depends on timely XPO1-mediated transport of specific protein and RNA cargoes. Using an immunosuppressed mouse model bearing primary patient-derived AML cells, we demonstrate that selinexor (KPT-330), an oral antagonist of XPO1 that is currently in clinical trials, has strong activity against primary AML cells while sparing normal stem and progenitor cells. Importantly, limiting dilution transplantation assays showed that this cytotoxic activity is not limited to the rapidly proliferating bulk population of leukemic cells but extends to the LICs, whose inherent drug resistance and unrestricted self-renewal capacity has been implicated in the difficulty of curing AML patients with conventional chemotherapy alone.

PMID:
26202935
PMCID:
PMC4994896
DOI:
10.1038/leu.2015.194
[Indexed for MEDLINE]
Free PMC Article

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