Selinexor synergizes with dexamethasone to repress mTORC1 signaling and induce multiple myeloma cell death

Abstract

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.

p27/Kip1 functions as a tumor suppressor and oncoprotein in osteosarcoma

“…Using the approach of selective inhibition of nuclear export (SINE) with siRNA mediated knockdown of XPO1, our results show that in order to execute its anti-apoptotic function, p27 protein must be stabilized in the nucleus and the combined inhibition of cell cycle progression and XPO1 activity, maintains p27 nuclear localization and promotes tumor suppressor function. These findings are of interest as SINE agents such as Selinexor show promising clinical activity against multiple myeloma growth 32 , bladder cancer 24 as well as other types of cancer that is mediated through the survivin pathway. Of note, Selinexor did not achieve single agent activity against the Pediatric Preclinical Testing Consortium osteosarcoma xenograft tumor panel 33 .…”

Targeting nuclear import and export in hematological malignancies

“…The combination of selinexor with dexamethasone, which achieved FDA approval, is also based on preclinical studies showing that XPO1 inhibition induces nuclear retention of phosphorylated glucocorticoid receptor, augmenting its activity. Combing dexamethasone with selinexor shows a synergistic effect with inhibition of the mTOR pathway and augmented myeloma cell death [ 54 ].…”

Selinexor‐based regimens for the treatment of myeloma refractory to chimeric antigen receptor T cell therapy

“…The anti‐myeloma activity seen in patients with disease that was refractory to bortezomib, carfilzomib and/or dexamethasone in a prior line of therapy validates reported data showing that selinexor overcomes resistance to proteasome inhibitors (PIs). Preclinical studies have demonstrated that selinexor synergizes with PIs and glucocorticoids through enhanced suppression of the NF‐κB signaling pathway and potentiation of glucocorticoid receptor transcriptional activity in the presence of dexamethasone, respectively (Kashyap et al , ; Argueta et al , ). These results are supported with clinical findings from the STOMP (NCT02343042) and NCT02199665 trials, which have demonstrated efficacy of Sd in combination with bortezomib or carfilzomib in patients with MM refractory to PIs (Bahlis et al , ; Jakubowiak et al , ).…”