2. Academic Validation
  3. Anti-tumor activity of selinexor in combination with antineoplastic agents in chronic lymphocytic leukemia

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

  • Sci Rep. 2023 Oct 7;13(1):16950. doi: 10.1038/s41598-023-44039-0.
Candida Vitale # 1 2,  Valentina Griggio # 1 2,  Maria Todaro 1 2,  Chiara Riganti 3,  Rebecca Jones 1 2,  Elia Boccellato 1 2,  Francesca Perutelli 1 2,  Francesca Arruga 4,  Tiziana Vaisitti 4,  Dimitar G Efremov 5,  Silvia Deaglio 4,  Yosef Landesman 6,  Benedetto Bruno 1 2,  Marta Coscia 7 8
Affiliations

Affiliations

  • 1 University Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, 10126, Turin, Italy.
  • 2 Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126, Turin, Italy.
  • 3 Department of Oncology, University of Torino, 10126, Turin, Italy.
  • 4 Department of Medical Sciences, University of Torino, 10126, Turin, Italy.
  • 5 Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, 34149, Trieste, Italy.
  • 6 Karyopharm Therapeutics, Newton, MA, 024559, USA.
  • 7 University Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, 10126, Turin, Italy. marta.coscia@unito.it.
  • 8 Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126, Turin, Italy. marta.coscia@unito.it.
  • # Contributed equally.
PMID: 37805613 DOI: 10.1038/s41598-023-44039-0
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 PI3Kδ 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 IkBα compared to each single compound. Finally, selinexor was also effective in potentiating the in vivo anti-tumor effects of the PI3Kδ 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 PI3Kδ in CLL.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12644
    99.98%, PI3K抑制剂
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