Reference - Detail
| RRC ID | 65503 |
|---|---|
| Author | Hing ZA, Mantel R, Beckwith KA, Guinn D, Williams E, Smith LL, Williams K, Johnson AJ, Lehman AM, Byrd JC, Woyach JA, Lapalombella R. |
| Title | Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia. |
| Journal | Blood |
| 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. |
| Volume | 125(20) |
| Pages | 3128-32 |
| Published | 2015-5-14 |
| DOI | 10.1182/blood-2015-01-621391 |
| PII | S0006-4971(20)31690-6 |
| PMID | 25838351 |
| PMC | PMC4432007 |
| MeSH | Adenine / analogs & derivatives Animals Antineoplastic Agents / administration & dosage Antineoplastic Agents / pharmacology* Cell Line, Tumor Cell Survival / drug effects Disease Models, Animal Drug Resistance, Neoplasm* Drug Synergism Humans Hydrazines / administration & dosage Hydrazines / pharmacology* Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy Leukemia, Lymphocytic, Chronic, B-Cell / mortality Leukemia, Lymphocytic, Chronic, B-Cell / pathology* Mice Piperidines Pyrazoles / administration & dosage Pyrazoles / pharmacology* Pyrimidines / administration & dosage Pyrimidines / pharmacology* Triazoles / administration & dosage Triazoles / pharmacology* Xenograft Model Antitumor Assays |
| IF | 17.794 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 17 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | Btk^(-) DT40(RCB1468) |