Oncotarget

Research Papers:

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

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

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2016; 7:16581-16592. https://doi.org/10.18632/oncotarget.7667

Metrics: PDF 1270 views  |   HTML 1905 views  |   ?  


Abstract

Robert Nakayama1,2, Yi-Xiang Zhang1, Jeffrey T. Czaplinski3, Alex J. Anatone3, Ewa T. Sicinska3, Jonathan A. Fletcher4, George D. Demetri1, Andrew J. Wagner1

1Ludwig Center at Dana-Farber/Harvard and Center for Sarcoma and Bone Oncology, Department of Medical Oncology, Harvard Medical School, Boston, MA, USA

2Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan

3Department of Medical Oncology and Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

4Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

Correspondence to:

Andrew J. Wagner, e-mail: Andrew_wagner@dfci.harvard.edu

Keywords: sarcoma, gastrointestinal stromal tumor, liposarcoma, selinexor, preclinical study

Received: November 22, 2015     Accepted: February 09, 2016     Published: February 24, 2016

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 7667