Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-κB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death

Abstract

The nuclear export protein, exportin-1 (XPO1/CRM1), is overexpressed in many cancers and correlates with poor prognosis. Selinexor, a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound, binds covalently to XPO1 and blocks its function. Treatment of cancer cells with selinexor results in nuclear retention of major tumor suppressor proteins and cell cycle regulators, leading to growth arrest and apoptosis. Recently, we described the selection of SINE compound resistant cells and reported elevated expression of inflammation-related genes in these cells. Here, we demonstrated that NF-κB transcriptional activity is up-regulated in cells that are naturally resistant or have acquired resistance to SINE compounds. Resistance to SINE compounds was created by knockdown of the cellular NF-κB inhibitor, IκB-α. Combination treatment of selinexor with proteasome inhibitors decreased NF-κB activity, sensitized SINE compound resistant cells and showed synergistic cytotoxicity in vitro and in vivo. Furthermore, we showed that selinexor inhibited NF-κB activity by blocking phosphorylation of the IκB-α and the NF-κB p65 subunits, protecting IκB-α from proteasome degradation and trapping IκB-α in the nucleus to suppress NF-κB activity. Therefore, combination treatment of selinexor with a proteasome inhibitor may be beneficial to patients with resistance to either single-agent.

Therapeutic Effects of XPO1 Inhibition in Thymic Epithelial Tumors

“…While loss of p53 activity can cause resistance to the XPO1 inhibitor under certain circumstances, other alterations such as XPO1 amplification may also contribute to the resistance. Our conclusions are also supported by other studies that indicated that in certain tumors, expression of certain TSPs is needed for selinexor sensitivity, whereas in other tumors, inactivation of these TSPs does not affect drug sensitivity (18,(31)(32)(33)(34).…”

Effect of miR-21 on Apoptosis in Lung Cancer Cell Through Inhibiting the PI3K/ Akt/NF-κB Signaling Pathway in Vitro and in Vivo

“…A previous study demonstrated that XPO1 inhibitor sensitivity to lung cancer was involved in the inhibition of NF-κB transcription factor activity [37]. Kashyap et al indicated that Selinexor showed significant anticancer activity against osteosarcoma by NF-kB inhibition [38]. We found that the miR-21 inhibitor inhibited the expression of P65 in a time-dependent manner.…”

Clinical Dosing Regimen of Selinexor Maintains Normal Immune Homeostasis and T-cell Effector Function in Mice: Implications for Combination with Immunotherapy

“…Effector CD8 T cells, despite no longer requiring costimulation, were also blocked in their capacity to degranulate or produce IFNγ when selinexor was present. Although we do not identify the exact proteins whose improper nuclear localization causes these effects on T cells, we suspect that several players contribute, including NF-κB, a heterodimeric transcription factor that is sequestered in the nucleus with its inhibitor IκBα upon blockade of XPO1 (28). Mice that overexpress IκBα show perturbations in thymic development, and a loss of CD8 T cells from the spleen and LNs (53), similar to the effects we observe in selinexor treated mice.…”

“…STAT3 is transported to the nucleus in its inactive conformation in non-cytokine stimulated cells, and addition of the XPO1 inhibitor leptomycin B leads to the accumulation of inactive STAT3 in the nucleus (25). NF-κB becomes trapped in the nucleus along with its inhibitor IκBα, leading to abrogation of activity upon treatment with selinexor or leptomycin B (5, 26–28). Other proteins of immunologic interest that rely on XPO1 for nuclear export include fyn, AID, AHR, and DGKζ, although it is unclear how loss of XPO1 function would affect the activity of these targets (21).…”