XPO1 inhibitor selinexor overcomes intrinsic ibrutinib resistance in mantle cell lymphoma via nuclear retention of IKB

Mei Ming, Wenjun Wu, Bingqing Xie, Madina Sukhanova, Weige Wang, Sabah Kadri, Shruti Sharma, Jimmy Lee, Sharon Shacham, Yosef Landesman, Natalia Maltsev, Pin Lu, Y. Lynn Wang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Inhibition 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.

Original languageEnglish (US)
Pages (from-to)2564-2574
Number of pages11
JournalMolecular cancer therapeutics
Volume17
Issue number12
DOIs
StatePublished - Dec 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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