Despite recent relevant therapeutic progresses, chronic lymphocytic leukemia (CLL) remains an incurable disease. Selinexor, an oral inhibitor of the nuclear export protein XPO1, is active as single agent in different hematologic malignancies, including CLL. The purpose of this study was to evaluate the anti-tumor effects of selinexor, used in combination with chemotherapy drugs (i.e. fludarabine and bendamustine) or with the PI3K delta inhibitor idelalisib in CLL. Our results showed a significant decrease in CLL cell viability after treatment with selinexor-containing drug combinations compared to each single compound, with demonstration of synergistic cytotoxic effects. Interestingly, this drug synergism was exerted also in the presence of the protective effect of stromal cells. From the molecular standpoint, the synergistic cytotoxic activity of selinexor plus idelalisib was associated with increased regulatory effects of this drug combination on the tumor suppressors FOXO3A and IkB alpha compared to each single compound. Finally, selinexor was also effective in potentiating the in vivo anti-tumor effects of the PI3K delta inhibitor in mice treated with the drug combination compared to single agents. Our data provide preclinical evidence of the synergism and potential efficacy of a combination treatment targeting XPO1 and PI3K delta in CLL.

Anti-tumor activity of selinexor in combination with antineoplastic agents in chronic lymphocytic leukemia

Vitale, Candida;Griggio, Valentina;Todaro, Maria;Riganti, Chiara;Jones, Rebecca;Boccellato, Elia;Perutelli, Francesca;Arruga, Francesca;Vaisitti, Tiziana;Deaglio, Silvia;Bruno, Benedetto;Coscia, Marta
2023-01-01

Abstract

Despite recent relevant therapeutic progresses, chronic lymphocytic leukemia (CLL) remains an incurable disease. Selinexor, an oral inhibitor of the nuclear export protein XPO1, is active as single agent in different hematologic malignancies, including CLL. The purpose of this study was to evaluate the anti-tumor effects of selinexor, used in combination with chemotherapy drugs (i.e. fludarabine and bendamustine) or with the PI3K delta inhibitor idelalisib in CLL. Our results showed a significant decrease in CLL cell viability after treatment with selinexor-containing drug combinations compared to each single compound, with demonstration of synergistic cytotoxic effects. Interestingly, this drug synergism was exerted also in the presence of the protective effect of stromal cells. From the molecular standpoint, the synergistic cytotoxic activity of selinexor plus idelalisib was associated with increased regulatory effects of this drug combination on the tumor suppressors FOXO3A and IkB alpha compared to each single compound. Finally, selinexor was also effective in potentiating the in vivo anti-tumor effects of the PI3K delta inhibitor in mice treated with the drug combination compared to single agents. Our data provide preclinical evidence of the synergism and potential efficacy of a combination treatment targeting XPO1 and PI3K delta in CLL.
2023
13
1
16950
16961
Selinexor, chronic lymphocytic leukemia, XPO1, PI3Kδ inhibitor, FOXO3A, IkBα
Vitale, Candida; Griggio, Valentina; Todaro, Maria; Riganti, Chiara; Jones, Rebecca; Boccellato, Elia; Perutelli, Francesca; Arruga, Francesca; Vaisitti, Tiziana; Efremov, Dimitar G; Deaglio, Silvia; Landesman, Yosef; Bruno, Benedetto; Coscia, Marta
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1945414
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