Abstract 1759: Preclinical activity of selinexor, an inhibitor of XPO1/CRM1, in sarcoma
Authors: Nakayama Robert , Zhang Yi-Xiang , Anatone Alex , Sicinska Ewa , Demetri George , Wagner Andrew 
Published: August 2015

Objective

Exportin 1/Chromosomal Region Maintenance Protein 1 (XPO1/CRM1) transports proteins bearing nuclear export signals from the cell nucleus to the cytoplasm. SINE are a family of small-molecules that selectively inhibit nuclear export through covalent binding to Cysteine 528 (Cys528) in the cargo binding pocket of XPO1. This leads to forced nuclear retention of cargo proteins that include major tumor suppressor proteins such as p53, FOXO, pRB and IkB. Preclinical and clinical studies have demonstrated selinexor activity in hematologic malignancies as well as in certain solid tumors, and it 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.

Materials and Methods

The efficacy of selinexor was tested in vitro and in vivo using 17 cell lines and 10 sarcoma xenograft models including gastrointestinal stromal tumor (GIST), liposarcoma (LPS), leiomyosarcoma, rhabdomyosarcoma, undifferentiated sarcomas, and alveolar soft part sarcoma (ASPS). Following exposure of cell lines to selinexor, effects on cell viability, cell cycle, and RNA and protein expression were determined. In sarcoma xenograft studies, selinexor was administered twice a week by oral gavage and changes in tumor size were recorded.

Results

Most sarcoma cell lines were sensitive to selinexor with IC50s ranging from 28.8 nM to 218.2 nM (median: 66.1 nM). The ASPS cell lines were exceptionally resistant to selinexor with IC50 greater than 2 μM. Selinexor suppressed sarcoma tumor xenograft growth, including models of ASPS that were resistant in vitro. Cell lines from several sarcoma subtypes with defined molecular backgrounds, such as GIST with KIT mutations and dedifferentiated LPS with MDM2 and CDK4 amplification, were treated with selinexor to investigate its mechanism of action. Selinexor induced G1 arrest in GIST cells without attenuation of phosphorylation of KIT, AKT, or MAPK, in contrast to imatinib. In LPS cell lines selinexor induced G1-arrest and apoptosis irrespective of p53 expression or mutation status and induced G1-arrest irrespective of RB expression. Selinexor increased p53 and p21 expression at the protein but not RNA levels, indicating a post-transcriptional effect.

Conclusions

Selinexor has potent in vitro and in vivo activity against a wide variety of sarcoma models. Selinexor induced 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.

Citation Format: Robert Nakayama, Yi-Xiang Zhang, Alex Anatone, Ewa Sicinska, George Demetri, Andrew Wagner. Preclinical activity of selinexor, an inhibitor of XPO1/CRM1, in sarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1759. doi:10.1158/1538-7445.AM2015-1759