American Association for Cancer Research
15357163mct181319-sup-212873_2_supp_5787626_py387z.pdf (31.94 kB)

Supp. Table 3 from Exportin 1 Inhibition Induces Nerve Growth Factor Receptor Expression to Inhibit the NF-κB Pathway in Preclinical Models of Pediatric High-Grade Glioma

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journal contribution
posted on 2023-04-03, 16:07 authored by John A. DeSisto, Patrick Flannery, Rakeb Lemma, Amrita Pathak, Shelby Mestnik, Natalie Philips, Natalie J. Bales, Trinayan Kashyap, Erin Moroze, Sujatha Venkataraman, Andrew L. Kung, Bruce D. Carter, Yosef Landesman, Rajeev Vibhakar, Adam L. Green

Summary of p-NF-KB and NF-KB values and ratios from Figure 1f, h and i


University of California

Dana-Farber Cancer Institute



TeamConnor Community Impact grant



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.