title: Longitudinal tracking of single live cancer cells to understand cell cycle effects of the nuclear export inhibitor, selinexor.
abstract: Longitudinal tracking is a powerful approach to understand the biology of single cells. In cancer therapy, outcome is determined at the molecular and cellular scale, yet relationships between cellular response and cell fate are often unknown. The selective inhibitor of nuclear export, selinexor, is in development for the treatment of various cancers. Selinexor covalently binds exportin-1, causing nuclear sequestration of cargo proteins, including key regulators of the cell cycle and apoptosis. The cell cycle effects of selinexor and the relationships between cell cycle effects and cell fates, has not been described for individual cells. Using fluorescent cell cycle indicators we report the majority of cell death after selinexor treatment occurs from a protracted G1-phase and early S-phase. G1- or early S-phase treated cells show the strongest response and either die or arrest, while those treated in late S- or G2-phase progress to mitosis and divide. Importantly, the progeny of cell divisions also die or arrest, mostly in the next G1-phase. Cells that survive selinexor are negative for multiple proliferation biomarkers, indicating a penetrant, arrested state. Selinexor acts quickly, shows strong cell cycle selectivity, and is highly effective at arresting cell growth and inducing death in cancer-derived cells.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, GOLD A240B, 347 UCB, University of Colorado-Boulder, Boulder, CO 80309 USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Marcus
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, GOLD A240B, 347 UCB, University of Colorado-Boulder, Boulder, CO 80309 USA.
authors.forename: Russell T
authors.initials: RT
authors.lastname: Burke
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, GOLD A240B, 347 UCB, University of Colorado-Boulder, Boulder, CO 80309 USA.
authors.forename: John A
authors.initials: JA
authors.lastname: DeSisto
authors.affiliation: Karyopharm Therapeutics, Inc., 85 Wells Ave., Newton, MA 02459.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Landesman
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, GOLD A240B, 347 UCB, University of Colorado-Boulder, Boulder, CO 80309 USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Orth
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D058948:Cell Tracking / Q000379:methods; D005456:Fluorescent Dyes; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D010641:Phenotype; D059010:Single-Cell Analysis; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D006834:Hydrazines; D014230:Triazoles; C585161:selinexor