XPO1 inhibition with selinexor synergizes with proteasome inhibition in neuroblastoma by targeting nuclear export of IkB

Abstract

Highlights XPO1 is overabundant in high-risk neuroblastoma and correlates with poor survival. Neuroblastoma cells are sensitive to XPO1 inhibition with selinexor. Use of selinexor results in nuclear retention of IkB, diminishing NF-kB activity. Selinexor and bortezomib act synergistically through promotion of apoptosis. Synergy is mediated in part, through IkB regulation of NF-kB activity.

Therapeutic Targeting of Exportin-1 in Childhood Cancer

“…Similar to findings in adult malignancies, XPO1 inhibitors in pediatric cancers have been found to induce a G1 cell cycle arrest, leading to a decrease in cells entering S/G2, in leukemia, neuroblastoma, MRT, and ATRT [ 30 , 89 , 90 , 91 , 95 ]. Further, XPO1-directed therapy has been shown to upregulate apoptosis in leukemia, high-grade glioma, ATRT, neuroblastoma, MRT, and sarcoma [ 30 , 89 , 90 , 91 , 93 , 94 , 95 ]. In acute leukemia, Etchin et al demonstrated the effect of KPT-185 on G1 cell cycle arrest and showed that the majority of apoptosis is induced at G1 [ 89 ].…”

“…In neuroblastoma, multimodal therapy is highly toxic and results in a cure rate for those with high-risk disease of approximately 50%, with substantial treatment-associated morbidity in survivors. Numerous publicly available gene expression datasets support the recently published findings from a proteomics screen in neuroblastoma that XPO1 is most highly expressed in patients with inferior outcome [ 30 ]. The numerous cargos transported by XPO1, including many affected by combination treatment and implicated in augmenting selinexor activity, reinforces current understand that no single agent or directed therapy can fully undermine the propensity of a cancer cell to survive.…”

“…Four selective inhibitors of nuclear export (SINE) compounds that reversibly bind XPO1, KPT-185, KPT-251, KPT-330 (selinexor), and SL-801 (felezonexor), have been explored across a range of malignancies. Preclinical evaluation of SINE compounds in specific childhood cancers dates back to at least 2012 with agents demonstrating low single-agent IC 50 concentrations across various pediatric leukemia subtypes [ 89 , 90 , 91 , 92 ], high-grade gliomas [ 92 , 93 ], atypical teratoid/rhabdoid tumor (ATRT) [ 92 ], malignant rhabdoid tumor (MRT) [ 92 ], sarcoma [ 92 , 94 ], neuroblastoma [ 30 , 92 ], and Wilms tumor [ 92 ]. Patient-derived xenograft (PDX) mouse models have shown encouraging anti-tumor activity and survival advantages in treated animals [ 89 , 90 , 91 , 92 ].…”

“…Based on these data, the combination of selinexor and proteasome inhibition is being explored in pediatric tumors, including neuroblastoma. Researchers demonstrated synergistic anti-cancer activity and increases in total apoptosis that were mediated by IkB nuclear localization induced by selinexor and diminished IkB degradation with bortezomib; they also identified synergistic functional inhibition of NF-kB transcriptional activity [ 30 ].…”

“…However, XPO1 transcript expression levels have not been generally predictive of response to targeted inhibition. Specifically in neuroblastoma, XPO1 protein expression and RNA expression do not correlate with sensitivity to selinexor [ 30 ]. However, recent efforts have explored XPO1 cargo localization and function, such as those listed in Table 1 , as predictors of response to XPO1 directed therapy [ 121 , 139 ].…”