Abstract 2074: Selective inhibitor of nuclear export (SINE) compounds show synergistic anti-tumor activity in combination with dexamethasone in multiple myeloma

Abstract

Abstract Background: The primary nuclear export protein, Exportin 1 (XPO1/CRM1), is overexpressed in most cancers, which is frequently correlated with poor prognosis. SINE compounds are small-molecule bioavailable drugs that bind covalently to XPO1, which leads to nuclear retention of major tumor suppressor proteins, such as p53, FOXO and IκB, resulting in selective cancer cell death. Selinexor is the most advanced SINE with >500 hematological and solid tumor cancer patients treated to date in Phase I/II clinical trials. Glucocorticoid Receptor (GR) is an XPO1 cargo and dexamethasone (Dex) acts through GR agonism and inhibition of NF-κB activity. The combination of selinexor with Dex seems likely to have enhanced anti-tumor potency and this hypothesis was tested in multiple myeloma models. Methods: Total RNA and whole protein cell lysates from multiple myeloma cell line (MM1S) treated with selinexor with or without dexamethasone were analyzed by quantitative PCR and by immunoblots. Localization of GR was evaluated by immunofluorescence. GR and NF-κB transcriptional activity was analyzed using ELISA assays. MM1S xenograft model in NOD-SCID mice were treated with selinexor with or without dexamethasone to evaluate the effect on tumor growth. Results: In MM.1S cells, we found Dex, but not selinexor, induced phosphorylation of GR resulting in GR nuclear localization. Selinexor prevented nuclear export of phosphorylated GR, leading to the synergistic induction of GR-dependent transcriptional activity. RNA levels of GR regulated genes such as MNK2 were induced by this combination treatment. Interestingly, between the two MNK2 isomers, the combination treatment increased the expression of MNK2α, which is a tumor suppressor protein but not the MNK2β isoform. NF-κB transcriptional activity was inhibited additively by this treatment in MM1S cells. The combination treatment of suboptimal doses of selinexor (5 mg/kg; 60% TGI) and Dex (1 mg/kg; 47% TGI) led to nearly complete growth suppression (91% TGI) in the MM1.S multiple myeloma xenografts. Conclusions: We confirmed the hypothesized synergistic anti-tumor activity for the combination of selinexor with dexamethasone and provided evidence that this synergy is mediated through enhanced GR transcriptional activity, inhibition NF-κB and upregulation of the tumor suppressor MNK2α. This work provides a rationale basis for conducting clinical trials of combinations of selinexor with dexamethasone against cancers known to be sensitive to dexamethasone, such as multiple myeloma. Promising anti tumor activity for the combination of selinexor and dexamethasone in patients with relapsed/refractory MM was reported in the ongoing Phase 1 study (NCT01607892). Citation Format: Yosef Landesman, Trinayan Kashyap, Boris Klebanov, Sivan Elloul, Marsha Crochiere, Sharon Friedlander, William Senapedis, Robert Carlson, Michael Kauffman, Sharon Shacham. Selective inhibitor of nuclear export (SINE) compounds show synergistic anti-tumor activity in combination with dexamethasone in multiple myeloma. [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 2074. doi:10.1158/1538-7445.AM2015-2074