title: 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.
authors.affiliation: Karyopharm Therapeutics Inc., Newton, MA, 02459, USA.
authors.forename: Trinayan
authors.initials: T
authors.lastname: Kashyap
authors.affiliation: Karyopharm Therapeutics Inc., Newton, MA, 02459, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Argueta
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Amro
authors.initials: A
authors.lastname: Aboukameel
authors.affiliation: Karyopharm Therapeutics Inc., Newton, MA, 02459, USA.
authors.forename: Thaddeus John
authors.initials: TJ
authors.lastname: Unger
authors.affiliation: Karyopharm Therapeutics Inc., Newton, MA, 02459, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Klebanov
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Ramzi M
authors.initials: RM
authors.lastname: Mohammad
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Irfana
authors.initials: I
authors.lastname: Muqbil
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Asfar S
authors.initials: AS
authors.lastname: Azmi
authors.affiliation: Karyopharm Therapeutics Inc., Newton, MA, 02459, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Drolen
authors.affiliation: Karyopharm Therapeutics Inc., Newton, MA, 02459, USA.
authors.forename: William
authors.initials: W
authors.lastname: Senapedis
authors.affiliation: Karyopharm Therapeutics Inc., Newton, MA, 02459, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Lee
authors.affiliation: Karyopharm Therapeutics Inc., Newton, MA, 02459, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kauffman
authors.affiliation: Karyopharm Therapeutics Inc., Newton, MA, 02459, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Karyopharm Therapeutics Inc., Newton, MA, 02459, USA.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Landesman
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D000069286:Bortezomib / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D000072000:NF-KappaB Inhibitor alpha / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D012516:Osteosarcoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D059748:Proteolysis; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology*; D000097606:Exportin 1 Protein
chemical_list: D000069286:Bortezomib; D006834:Hydrazines; D028884:Karyopherins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D051996:Transcription Factor RelA; D014230:Triazoles; D000097606:Exportin 1 Protein; C000606204:NFKBIA protein, human; C498143:RELA protein, human; C585161:selinexor
keywords: NF-κB; SINE; XPO1; proteasome inhibitors; selinexor