Purpose:Selinexor, a small molecule that inhibits nuclear export protein XPO1 has demonstrated efficacy in solid tumors and hematologic malignancies with the evidence of clinical activity in sarcoma as a single agent. Treatment options available are very few and hence the need to identify novel targets and strategic therapies is of utmost importance. Experimental Design:: The mechanistic effects of selinexor in sarcomas as a monotherapy and in combination with proteasome inhibitor, carfilzomib, across a panel of cell lines in vitro and few in xenograft mouse models were investigated. Results:Selinexor induced IkappaB nuclear localization as a single agent and the effect was enhanced by stabilization of IkappaB when pretreated with the proteasome inhibitor carfilzomib. This stabilization and retention of IkappaB in the nucleus resulted in inhibition of NFkappaB and transcriptional suppression of the critical anti-apoptotic protein, survivin. Treatment of carfilzomib followed by selinexor caused selinexor-sensitive and selinexor-resistant cell lines to be more sensitive to selinexor as determined by an increase in apoptosis. This was successfully demonstrated in MPNST xenograft model with enhanced tumor suppression. Conclusions:The subcellular distributions of IkappaB and NFkappaB are indicative of carcinogenesis. Inhibition of XPO1 results in intra-nuclear retention of IkappaB which inhibits NFkappaB and thereby provides a novel mechanism for drug therapy in sarcoma. This effect can be further enhanced in relatively selinexor-resistant sarcoma cell lines by pre-treatment with proteasome inhibitor, carfilzomib. Because of these results, a human clinical trial with selinexor in combination with a proteasome inhibitor is planned for the treatment of sarcoma.
- Received October 19, 2016.
- Revision received March 9, 2017.
- Accepted March 10, 2017.
- Copyright ©2017, American Association for Cancer Research.