XPO1 Inhibitor Selinexor Overcomes Intrinsic Ibrutinib Resistance in Mantle Cell Lymphoma via Nuclear Retention of I kappa B

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 NF kappa B gene signature, as opposed to BCR signature, was a common feature that underlies the response of MCL to both selinexor and ibrutinib. Meanwhile, unaltered NF kappa B was associated with ibrutinib resistance. Mechnistically, selinexor induced nuclear retention of I kappa B that was accompanied by the reduction of DNA-binding activity of NF kappa B, suggesting that NF kappa B is trapped in an inhibitory complex. Coimmunoprecipitation confirmed that p65 of NF kappa B and I kappa B were physically associated. In primary MCL tumors, we further demonstrated that the number of cells with I kappa B nuclear retention was linearly correlated with the degree of apoptosis. Our data highlight the role of NF kappa B pathway in drug response to ibrutinib and selinexor and show the potential of using selinexor to prevent and over-come intrinsic ibrutinib resistance through NF kappa B inhibition. (C) 2018 AACR.