Molecular targets for therapy

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

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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.

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We thank the patients for their cooperation in providing bone marrow samples for this study; Ilene Galinsky for providing the patient samples used to generate mouse PDX models of human AML; Nancy Kohl, Paul Kirschmeier and Prafulla Gokhale for assistance in guiding in vivo studies at the Lurie Family Imaging Center; John Gilbert for his editorial review and critical reading of the manuscript; and John Daley and the flow cytometry team for their valuable advice. This research was supported by William Lawrence and Blanche Hughes Foundation (to ATL), Leukemia and Lymphoma Society’s Translational research grant (to ATL), Alex’s Lemonade Stand Foundation’s Young Research Investigator grant (to JE), Luck2Tuck Foundation (to JE), Claudia Adams Barr Innovative Basic Science Research grant (to MRM) and Lady Tata Memorial Trust (to CELN).

Author contributions

JE designed and performed experiments, analyzed data and wrote the manuscript. BTL and AB performed experiments and analyzed data. ALC, CR and AB helped design and perform in vivo mouse studies. AK, MRM, CELN and SA participated in experimental design and data analysis. SS and MK designed the KPT-330 compound and participated in the design of in vivo mouse studies. IAG and RMS provided AML patient samples and helped to analyze the data. SJR interpreted the hematopathology. BK, YL, WCC, JCYW and ALK designed experiments and analyzed the data. JM and AL designed and performed BH3 profiling experiments and analyzed data. ATL guided the research, analyzed the results and wrote the paper.

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Correspondence to A T Look.

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Competing interests

BK, SS, MK and YL are employees of Karyopharm Therapeutics Incorporated and receive compensation and hold equity in the company. The other authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Leukemia website

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