Ming MWu WXie BSukhanova MWang WKadri SSharma SLee JShacham SLandesman YMaltsev NLu PLynn Wang Y.LI-HSING LEE2022-11-112022-11-11201815357163https://www.scopus.com/inward/record.uri?eid=2-s2.0-85057592111&doi=10.1158%2f1535-7163.MCT-17-0789-ATR&partnerID=40&md5=a429d15e0dd4b21d22e8884bc922fa29https://scholars.lib.ntu.edu.tw/handle/123456789/624845Inhibition of B-cell receptor (BCR) signaling through the BTK inhibitor, ibrutinib, has generated a remarkable response in mantle cell lymphoma (MCL). However, approximately one third of patients do not respond well to the drug, and disease relapse on ibrutinib is nearly universal. Alternative therapeutic strategies aimed to prevent and overcome ibrutinib resistance are needed. We compared and contrasted the effects of selinexor, a selective inhibitor of nuclear export, with ibrutinib in six MCL cell lines that display differential intrinsic sensitivity to ibrutinib. We found that selinexor had a broader antitumor activity in MCL than ibrutinib. MCL cell lines resistant to ibrutinib remained sensitive to selinexor. We showed that selinexor induced apoptosis/cell-cycle arrest and XPO-1 knockdown also retarded cell growth. Furthermore, downregulation of the NFkB gene signature, as opposed to BCR signature, was a common feature that underlies the response of MCL to both selinexor and ibrutinib. Meanwhile, unaltered NFkB was associated with ibrutinib resistance. Mechnistically, selinexor induced nuclear retention of IkB that was accompanied by the reduction of DNA-binding activity of NFkB, suggesting that NFkB is trapped in an inhibitory complex. Coimmunoprecipitation confirmed that p65 of NFkB and IkB were physically associated. In primary MCL tumors, we further demonstrated that the number of cells with IkB nuclear retention was linearly correlated with the degree of apoptosis. Our data highlight the role of NFkB pathway in drug response to ibrutinib and selinexor and show the potential of using selinexor to prevent and overcome intrinsic ibrutinib resistance through NFkB inhibition. © 2018 American Association for Cancer Research.exportin 1; I kappa B; ibrutinib; immunoglobulin enhancer binding protein; selinexor; transcription factor RelA; cell receptor; exportin 1 protein; hydrazine derivative; I kappa B; ibrutinib; immunoglobulin enhancer binding protein; karyopherin; pyrazole derivative; pyrimidine derivative; selinexor; triazole derivative; antineoplastic activity; apoptosis; Article; cancer research; cell cycle arrest; cell nucleus; cell proliferation; cellular distribution; controlled study; down regulation; drug potentiation; drug resistance; drug sensitivity; female; gene knockdown; growth inhibition; human; human cell; human tissue; IC50; immunoprecipitation; male; mantle cell lymphoma; mantle cell lymphoma cell; nuclear export; priority journal; protein DNA binding; protein localization; cell nucleus; drug effect; mantle cell lymphoma; metabolism; protein subunit; tumor cell line; Apoptosis; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Down-Regulation; Drug Resistance, Neoplasm; Humans; Hydrazines; I-kappa B Proteins; Karyopherins; Lymphoma, Mantle-Cell; NF-kappa B; Protein Subunits; Pyrazoles; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Triazolesjournal article10.1158/1535-7163.MCT-17-0789-ATR305101422-s2.0-85057592111