Selinexor (KPT-330) Induces Tumor Suppression through Nuclear Sequestration of IκB and Downregulation of Survivin.
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 linesin vitroand few in xenograft mouse models were investigated.Results:Selinexor induced IκB nuclear localization as a single agent, and the effect was enhanced by stabilization of IκB when pretreated with the proteasome inhibitor carfilzomib. This stabilization and retention of IκB in the nucleus resulted in inhibition of NFκB and transcriptional suppression of the critical antiapoptotic 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 the MPNST xenograft model with enhanced tumor suppression.Conclusions:The subcellular distributions of IκB and NFκB are indicative of carcinogenesis. Inhibition of XPO1 results in intranuclear retention of IκB, which inhibits NFκB 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 pretreatment with the 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.Clin Cancer Res; 23(15); 4301-11. ©2017 AACR.
Columbia University Medical Center, Herbert Irving Comprehensive Cancer Center, New York, New York. jayasree_nair@hotmail.com.
Jayasree S
JS
Nair
Columbia University Medical Center, Herbert Irving Comprehensive Cancer Center, New York, New York.
Elgilda
E
Musi
Columbia University Medical Center, Herbert Irving Comprehensive Cancer Center, New York, New York.
Gary K
GK
Schwartz
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage*; D020672:I-kappa B Proteins / Q000235:genetics*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D028884:Karyopherins / Q000037:antagonists & inhibitors / Q000235:genetics*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics; D009842:Oligopeptides / Q000008:administration & dosage; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics*; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077022:Survivin; D051996:Transcription Factor RelA / Q000235:genetics; D014230:Triazoles / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays; D000097606:Exportin 1 Protein
D006834:Hydrazines; D020672:I-kappa B Proteins; D051034:Inhibitor of Apoptosis Proteins; D028884:Karyopherins; D016328:NF-kappa B; D009842:Oligopeptides; D018160:Receptors, Cytoplasmic and Nuclear; D000077022:Survivin; D051996:Transcription Factor RelA; D014230:Triazoles; D000097606:Exportin 1 Protein; C107489:BIRC5 protein, human; C498143:RELA protein, human; C585161:selinexor; C524865:carfilzomib