Selinexor synergizes with dexamethasone to repress mTORC1 signaling and induce multiple myeloma cell death
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Christian Argueta1,*, Trinayan Kashyap1,*, Boris Klebanov1, Thaddeus J. Unger1, Cathy Guo1, Susie Harrington1, Erkan Baloglu1, Margaret Lee1, William Senapedis1, Sharon Shacham1 and Yosef Landesman1
1Karyopharm Therapeutics Inc, Newton, MA 02459, USA
*These authors contributed equally to this work
Christian Argueta, email: [email protected]
Keywords: exportin-1; selinexor; glucocorticoid receptor; mTOR
Received: January 24, 2018 Accepted: April 25, 2018 Published: May 22, 2018
Multiple myeloma (MM) is a plasma cell neoplasm that results in over 11,000 deaths in the United States annually. The backbone therapy for the treatment of MM patients almost always includes combinations with corticosteroids such as dexamethasone (DEX). We found that DEX in combination with selinexor, an inhibitor of exportin-1 (XPO1) activity, synergistically inhibits the mTOR pathway and subsequently promotes cell death in MM cells. Specifically, we show that selinexor induces the expression of the glucocorticoid receptor (GR) and when combined with dexamethasone increases GR transcriptional activity. Moreover, we found that key downstream targets of the mTOR pathway are deregulated by the combination and identified a mechanism in which GR enhances the expression of REDD1 in GR positive cells while suppressing mTOR activity and cell viability. While the single agent activity of selinexor in MM cells appears to be GR-independent, synergy with DEX depends on GR expression. These data suggest that patients with tumor cells that are GR positive will benefit substantially from the combination. The current findings are consistent with the beneficial therapeutic outcome in patients with MM when treated with the combination of selinexor and DEX. In addition, they provide a rationale for testing GR and REDD1 as predictive and prognostic markers of response, respectively, for patients treated with this beneficial combination.
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