title: Activity of a selective inhibitor of nuclear export, selinexor (KPT-330), against AML-initiating cells engrafted into immunosuppressed NSG mice.
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.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.|Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Etchin
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Montero
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Berezovskaya
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
authors.forename: B T
authors.initials: BT
authors.lastname: Le
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: A
authors.identifier: http://orcid.org/0000-0002-8063-9191
authors.initials: A
authors.lastname: Kentsis
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Christie
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Conway
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: W C
authors.initials: WC
authors.lastname: Chen
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
authors.forename: C
authors.identifier: http://orcid.org/0000-0001-9012-3183
authors.initials: C
authors.lastname: Reed
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.|Department of Haematology, UCL Cancer Institute, University College London, London, UK.
authors.forename: M R
authors.initials: MR
authors.lastname: Mansour
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
authors.forename: C E L
authors.initials: CE
authors.lastname: Ng
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Adamia
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Rodig
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA.
authors.forename: I A
authors.initials: IA
authors.lastname: Galinsky
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Stone
authors.affiliation: Karyopharm Therapeutics, Natick, MA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Klebanov
authors.affiliation: Karyopharm Therapeutics, Natick, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Landesman
authors.affiliation: Karyopharm Therapeutics, Natick, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kauffman
authors.affiliation: Karyopharm Therapeutics, Natick, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Medical Center, New York, NY, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Kung
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: J C Y
authors.initials: JC
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Letai
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.|Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Look
mesh_terms: D000818:Animals; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D007165:Immunosuppression Therapy; D028884:Karyopherins / Q000037:antagonists & inhibitors*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000097606:Exportin 1 Protein
chemical_list: D006834:Hydrazines; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D000097606:Exportin 1 Protein; C585161:selinexor