Activity of a selective inhibitor of nuclear export, selinexor (KPT-330), against AML-initiating cells engrafted into immunosuppressed NSG mice.
J EtchinJ MonteroA BerezovskayaB T LeAlex KentsisA L ChristieA S ConwayW C ChenC ReedM R MansourC E L NgS AdamiaS J RodigI A GalinskyR M StoneB KlebanovY LandesmanM KauffmanS ShachamA L KungJ C Y WangA LetaiA T LookPublished in: Leukemia (2015)
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.
Keyphrases
- acute myeloid leukemia
- induced apoptosis
- cell cycle arrest
- clinical trial
- mouse model
- endoplasmic reticulum stress
- allogeneic hematopoietic stem cell transplantation
- type diabetes
- metabolic syndrome
- small molecule
- acute lymphoblastic leukemia
- stem cells
- cell death
- mesenchymal stem cells
- insulin resistance
- ms ms
- minimally invasive
- liquid chromatography
- tandem mass spectrometry
- phase iii
- phase ii