Preclinical activity of selinexor, an inhibitor of XPO1, in sarcoma

Turrent Robert Nakayama, Yi Xiang Zhang, Jeffrey T. Czaplinski, Alex J. Anatone, Ewa T. Sicinska, Jonathan A. Fletcher, George D. Demetri, Andrew J. Wagner

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Selinexor is an orally bioavailable selective inhibitor of nuclear export that has been demonstrated to have preclinical activity in various cancer types and that is currently in Phase I and II clinical trials for advanced cancers. In this study, we evaluated the effects of selinexor in several preclinical models of various sarcoma subtypes. The efficacy of selinexor was investigated in vitro and in vivo using 17 cell lines and 9 sarcoma xenograft models including gastrointestinal stromal tumor (GIST), liposarcoma (LPS), leiomyosarcoma, rhabdomyosarcoma, undifferentiated sarcomas, and alveolar soft part sarcoma (ASPS). Most sarcoma cell lines were sensitive to selinexor with IC50s ranging from 28.8 nM to 218.2 nM (median: 66.1 nM). Selinexor suppressed sarcoma tumor xenograft growth, including models of ASPS that were resistant in vitro. In GIST cells with KIT mutations, selinexor induced G1- arrest without attenuation of phosphorylation of KIT, AKT, or MAPK, in contrast to imatinib. In LPS cell lines with MDM2 and CDK4 amplification, selinexor induced G1-arrest and apoptosis irrespective of p53 expression or mutation and irrespective of RB expression. Selinexor increased p53 and p21 expression at the protein but not RNA level, indicating a post-transcriptional effect. These results indicate that selinexor has potent in vitro and in vivo activity against a wide variety of sarcoma models by inducing G1-arrest independent of known molecular mechanisms in GIST and LPS. These studies further justify the exploration of selinexor in clinical trials targeting various sarcoma subtypes.

Original languageEnglish
Pages (from-to)16581-16592
Number of pages12
JournalOncotarget
Volume7
Issue number13
DOIs
Publication statusPublished - 2016 Mar 29

Fingerprint

Sarcoma
Liposarcoma
Gastrointestinal Stromal Tumors
Alveolar Soft Part Sarcoma
Heterografts
Cell Line
KPT-330
Neoplasms
Phase II Clinical Trials
Clinical Trials, Phase I
Mutation
Cell Nucleus Active Transport
Leiomyosarcoma
Rhabdomyosarcoma
Stromal Cells
Phosphorylation
Clinical Trials
RNA
Apoptosis
Growth

Keywords

  • Gastrointestinal stromal tumor
  • Liposarcoma
  • Preclinical study
  • Sarcoma
  • Selinexor

ASJC Scopus subject areas

  • Oncology

Cite this

Nakayama, T. R., Zhang, Y. X., Czaplinski, J. T., Anatone, A. J., Sicinska, E. T., Fletcher, J. A., ... Wagner, A. J. (2016). Preclinical activity of selinexor, an inhibitor of XPO1, in sarcoma. Oncotarget, 7(13), 16581-16592. https://doi.org/10.18632/oncotarget.7667

Preclinical activity of selinexor, an inhibitor of XPO1, in sarcoma. / Nakayama, Turrent Robert; Zhang, Yi Xiang; Czaplinski, Jeffrey T.; Anatone, Alex J.; Sicinska, Ewa T.; Fletcher, Jonathan A.; Demetri, George D.; Wagner, Andrew J.

In: Oncotarget, Vol. 7, No. 13, 29.03.2016, p. 16581-16592.

Research output: Contribution to journalArticle

Nakayama, TR, Zhang, YX, Czaplinski, JT, Anatone, AJ, Sicinska, ET, Fletcher, JA, Demetri, GD & Wagner, AJ 2016, 'Preclinical activity of selinexor, an inhibitor of XPO1, in sarcoma', Oncotarget, vol. 7, no. 13, pp. 16581-16592. https://doi.org/10.18632/oncotarget.7667
Nakayama TR, Zhang YX, Czaplinski JT, Anatone AJ, Sicinska ET, Fletcher JA et al. Preclinical activity of selinexor, an inhibitor of XPO1, in sarcoma. Oncotarget. 2016 Mar 29;7(13):16581-16592. https://doi.org/10.18632/oncotarget.7667
Nakayama, Turrent Robert ; Zhang, Yi Xiang ; Czaplinski, Jeffrey T. ; Anatone, Alex J. ; Sicinska, Ewa T. ; Fletcher, Jonathan A. ; Demetri, George D. ; Wagner, Andrew J. / Preclinical activity of selinexor, an inhibitor of XPO1, in sarcoma. In: Oncotarget. 2016 ; Vol. 7, No. 13. pp. 16581-16592.
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