Selinexor (KPT-330) Induces Tumor Suppression through Nuclear Sequestration of IκB and Downregulation of Survivin

Abstract

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 IkB nuclear localization as a single agent, and the effect was enhanced by stabilization of IkB when pretreated with the proteasome inhibitor carfilzomib. This stabilization and retention of IkB in the nucleus resulted in inhibition of NFkB 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 IkB and NFkB are indicative of carcinogenesis. Inhibition of XPO1 results in intranuclear retention of IkB, which inhibits NFkB 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.

The effect of CRM1 inhibition on human non-Hodgkin lymphoma cells

“…Consistent with previous studies of KPT-330 on acute myeloid leukemia, our studies of KPT-330 in NHL showed induction of G1 cell cycle arrest in MCL and TCL 9 . As was shown in sarcoma and MCL in previous studies, we also found that MCL cells have increased IkB localization in the nucleus with KPT-330 treatment 10,11 . In recent studies, it was found that bortezomib and DNA damaging agents such as gemcitabine impose a synergistic antitumor effect when combined with KPT-330 in solid tumors such as sarcoma and breast cancer, and hematologic malignancies such as AML, MM, and DLBCL [4][5][6]8,12 .…”

Mechanisms underlying synergy between DNA topoisomerase I-targeted drugs and mTOR kinase inhibitors in NF1-associated malignant peripheral nerve sheath tumors

“…We also tested vincristine and cyclophosphamide because of their inclusion in an effective chemotherapy regimen for softtissue sarcomas [40]. The nuclear transporter XPO1 inhibitor KPT-330 was included in the candidate list because it showed antitumor activity against MPNSTs [41], KRASdriven lung cancer [42], and T-cell acute lymphoblastic leukemia harboring activating mutations of NRAS and NOTCH1 [43]. Finally, etoposide and topotecan were considered potentially useful drugs because of their activity in the treatment of advanced soft-tissue sarcomas, alone or in combination with other agents [44,45].…”

Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma

“…Preclinical studies have provided a rationale for combining selinexor with PIs (Kashyap et al , ; Nair et al , ; Rosebeck et al , ; Turner et al , ). The addition of selinexor to a PI has a synergistic effect on cell death of myeloma cell lines and primary plasma cells derived from patients with RRMM, and the combination demonstrated greater antimyeloma activity in a murine xenograft model than either agent alone (Kashyap et al , ; Rosebeck et al , ; Turner et al , ).…”