Exportin 1 inhibition induces nerve growth factor receptor expression to inhibit the NF-κB pathway in preclinical models of pediatric high-grade glioma Journal Article


Authors: DeSisto, J. A.; Flannery, P.; Lemma, R.; Pathak, A.; Mestnik, S.; Philips, N.; Bales, N. J.; Kashyap, T.; Moroze, E.; Venkataraman, S.; Kung, A. L.; Carter, B. D.; Landesman, Y.; Vibhakar, R.; Green, A. L.
Article Title: Exportin 1 inhibition induces nerve growth factor receptor expression to inhibit the NF-κB pathway in preclinical models of pediatric high-grade glioma
Abstract: High-grade glioma (HGG) is the leading cause of cancer-related death among children. Selinexor, an orally bioavailable, reversible inhibitor of the nuclear export protein, exportin 1, is in clinical trials for a range of cancers, including HGG. It inhibits the NF-κB pathway and strongly induces the expression of nerve growth factor receptor (NGFR) in preclinical cancer models. We hypothesized that selinexor inhibits NF-κB via upregulation of NGFR. In HGG cells, sensitivity to selinexor correlated with increased induction of cell surface NGFR expression. Knocking down NGFR in HGG cells increased proliferation, anchorage-independent growth, stemness markers, and levels of transcriptionally available nuclear NF-κB not bound to IκB-α, while decreasing apoptosis and sensitivity to selinexor. Increasing IκB-α levels in NGFR knockdown cells restored sensitivity to selinexor. Overexpression of NGFR using cDNA reduced levels of free nuclear NF-κB, decreased stemness markers, and increased markers of cellular differentiation. In all HGG lines tested, selinexor decreased phosphorylation of NF-κB at serine 536 (a site associated with increased transcription of proliferative and inflammatory genes). Because resistance to selinexor monotherapy occurred in our in vivo model, we screened selinexor with a panel of FDA-approved anticancer agents. Bortezomib, a proteasome inhibitor that inhibits the NF-κB pathway through a different mechanism than selinexor, showed synergy with selinexor against HGG in vitro Our results help elucidate selinexor's mechanism of action and identify NGFR as a potential biomarker of its effect in HGG and in addition suggest a combination therapy strategy for these challenging tumors. ©2019 American Association for Cancer Research.
Journal Title: Molecular Cancer Therapeutics
Volume: 19
Issue: 2
ISSN: 1535-7163
Publisher: American Association for Cancer Research  
Date Published: 2020-02-01
Start Page: 540
End Page: 551
Language: English
DOI: 10.1158/1535-7163.Mct-18-1319
PUBMED: 31594826
PROVIDER: scopus
PMCID: PMC7007851
DOI/URL:
Notes: Article -- Export Date: 2 March 2020 -- Source: Scopus
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  1. Andrew L Kung
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