title: Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia.
abstract: Despite the therapeutic efficacy of ibrutinib in chronic lymphocytic leukemia (CLL), complete responses are infrequent, and acquired resistance to Bruton agammaglobulinemia tyrosine kinase (BTK) inhibition is being observed in an increasing number of patients. Combination regimens that increase frequency of complete remissions, accelerate time to remission, and overcome single agent resistance are of considerable interest. We previously showed that the XPO1 inhibitor selinexor is proapoptotic in CLL cells and disrupts B-cell receptor signaling via BTK depletion. Herein we show the combination of selinexor and ibrutinib elicits a synergistic cytotoxic effect in primary CLL cells and increases overall survival compared with ibrutinib alone in a mouse model of CLL. Selinexor is effective in cells isolated from patients with prolonged lymphocytosis following ibrutinib therapy. Finally, selinexor is effective in ibrutinib-refractory mice and in a cell line harboring the BTK C481S mutation. This is the first report describing the combined activity of ibrutinib and selinexor in CLL, which represents a new treatment paradigm and warrants further evaluation in clinical trials of CLL patients including those with acquired ibrutinib resistance.
authors.affiliation: Medical Scientist Training Program, Division of Hematology, Department of Internal Medicine.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Hing
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Rose
authors.initials: R
authors.lastname: Mantel
authors.affiliation: Medical Scientist Training Program, Division of Hematology, Department of Internal Medicine.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Beckwith
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Daphne
authors.initials: D
authors.lastname: Guinn
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Erich
authors.initials: E
authors.lastname: Williams
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Smith
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Katie
authors.initials: K
authors.lastname: Williams
authors.affiliation: Division of Hematology, Department of Internal Medicine, Division of Medicinal Chemistry, College of Pharmacy, and.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, OH.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Lehman
authors.affiliation: Division of Hematology, Department of Internal Medicine, Division of Medicinal Chemistry, College of Pharmacy, and.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Woyach
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Rosa
authors.initials: R
authors.lastname: Lapalombella
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D051379:Mice; D010880:Piperidines; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006834:Hydrazines; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D014230:Triazoles; C551803:ibrutinib; C585161:selinexor; D000225:Adenine
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