Oncotarget

Research Papers:

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

Trinayan Kashyap, Christian Argueta, Amro Aboukameel, Thaddeus John Unger, Boris Klebanov, Ramzi M. Mohammad, Irfana Muqbil, Asfar S. Azmi, Claire Drolen, William Senapedis, Margaret Lee, Michael Kauffman, Sharon Shacham and Yosef Landesman _

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Oncotarget. 2016; 7:78883-78895. https://doi.org/10.18632/oncotarget.12428

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Abstract

Trinayan Kashyap1, Christian Argueta1, Amro Aboukameel2, Thaddeus John Unger1, Boris Klebanov1, Ramzi M. Mohammad2, Irfana Muqbil2, Asfar S. Azmi2, Claire Drolen1, William Senapedis1, Margaret Lee1, Michael Kauffman1, Sharon Shacham1, Yosef Landesman1

1Karyopharm Therapeutics Inc., Newton, MA, 02459, USA

2Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA

Correspondence to:

Trinayan Kashyap, email: tkashyap@karyopharm.com

Keywords: SINE, selinexor, XPO1, NF-κB, proteasome inhibitors

Received: July 25, 2016     Accepted: September 22, 2016     Published: October 04, 2016

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.


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