| RRC ID |
65503
|
| 著者 |
Hing ZA, Mantel R, Beckwith KA, Guinn D, Williams E, Smith LL, Williams K, Johnson AJ, Lehman AM, Byrd JC, Woyach JA, Lapalombella R.
|
| タイトル |
Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia.
|
| ジャーナル |
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.
|
| 巻・号 |
125(20)
|
| ページ |
3128-32
|
| 公開日 |
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
|
| リソース情報 |
| ヒト・動物細胞 |
Btk^(-) DT40(RCB1468) |
