selinexor and Lymphoma--Mantle-Cell

Chromosome region maintenance protein 1 (CRM1) mediates protein export from the nucleus and is a new target for anticancer therapeutics. Broader application of KPT-330 (selinexor), a first-in-class CRM1 inhibitor recently approved for relapsed multiple myeloma and diffuse large B-cell lymphoma, have been limited by substantial toxicity. We discovered that salicylates markedly enhance the antitumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. Using salicylates in combination enables targeting of a range of blood cancers with a much lower dose of selinexor, thereby potentially mitigating prohibitive clinical adverse effects. Choline salicylate (CS) with low-dose KPT-330 (K+CS) had potent, broad activity across high-risk hematological malignancies and solid-organ cancers ex vivo and in vivo. The K+CS combination was not toxic to nonmalignant cells as compared with malignant cells and was safe without inducing toxicity to normal organs in mice. Mechanistically, compared with KPT-330 alone, K+CS suppresses the expression of CRM1, Rad51, and thymidylate synthase proteins, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, cell-cycle arrest in S-phase, and cell apoptosis. Moreover, the addition of poly (ADP-ribose) polymerase inhibitors further potentiates the K+CS antitumor effect. K+CS represents a new class of therapy for multiple types of blood cancers and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for cancer therapy in general.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle Checkpoints; Choline; DNA Repair; DNA Replication; DNA, Neoplasm; Drug Combinations; Drug Synergism; Exportin 1 Protein; Gene Expression Regulation, Neoplastic; Humans; Hydrazines; Karyopherins; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Proteins; Phthalazines; Piperazines; Random Allocation; Receptors, Cytoplasmic and Nuclear; S Phase Cell Cycle Checkpoints; Salicylates; Triazoles; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Drug Synergism; Humans; Hydrazines; Lymphoma, B-Cell; Lymphoma, Mantle-Cell; Niacinamide; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides; Triazoles; Tumor Cells, Cultured

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

Topics: Adenine; Apoptosis; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Down-Regulation; Drug Resistance, Neoplasm; Exportin 1 Protein; Humans; Hydrazines; I-kappa B Proteins; Karyopherins; Lymphoma, Mantle-Cell; NF-kappa B; Piperidines; Protein Subunits; Pyrazoles; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Triazoles