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| Item Type: | Article |
|---|---|
| Title: | Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma |
| Creators: |
Rahal, R., Frick, M., Romero, R., Korn, J.M., Kridel, R., Chun Chan, F., Meissner, B., Bhang, H.E., Ruddy, D., Kauffmann, A., Farsidjani, A., Derti, A., Rakiec, D., Naylor, T., Pfister, E., Kovats, S., Kim, S., Dietze, K., Doerken, B.  ORCID: https://orcid.org/0000-0001-7991-3643, Steidl, C., Tzankov, A., Hummel, M., Monahan, J., Morrissey, M.P., Fritsch, C., Sellers, W.R., Cooke, V.G., Gascoyne, R.D., Lenz, G. and Stegmeier, F.
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| Abstract: | Mantle cell lymphoma (MCL) is an aggressive malignancy that is characterized by poor prognosis. Large-scale pharmacological profiling across more than 100 hematological cell line models identified a subset of MCL cell lines that are highly sensitive to the B cell receptor (BCR) signaling inhibitors ibrutinib and sotrastaurin. Sensitive MCL models exhibited chronic activation of the BCR-driven classical nuclear factor-{kappa}B (NF-{kappa}B) pathway, whereas insensitive cell lines displayed activation of the alternative NF-{kappa}B pathway. Transcriptome sequencing revealed genetic lesions in alternative NF-{kappa}B pathway signaling components in ibrutinib-insensitive cell lines, and sequencing of 165 samples from patients with MCL identified recurrent mutations in TRAF2 or BIRC3 in 15% of these individuals. Although they are associated with insensitivity to ibrutinib, lesions in the alternative NF-{kappa}B pathway conferred dependence on the protein kinase NIK (also called mitogen-activated protein 3 kinase 14 or MAP3K14) both in vitro and in vivo. Thus, NIK is a new therapeutic target for MCL treatment, particularly for lymphomas that are refractory to BCR pathway inhibitors. Our findings reveal a pattern of mutually exclusive activation of the BCR-NF-{kappa}B or NIK-NF-{kappa}B pathways in MCL and provide critical insights into patient stratification strategies for NF-{kappa}B pathway-targeted agents. |
| Keywords: | Base Sequence, Western Blotting, CARD Signaling Adaptor Proteins, Cell Line, Cell Survival, DNA Primers, Guanylate Cyclase, Inhibitor of Apoptosis Proteins, Luminescent Measurements, Mantle-Cell Lymphoma, Microarray Analysis, Molecular Sequence Data, NF-kappa B, Protein-Serine-Threonine Kinases, Pyrazoles, Pyrimidines, Pyrroles, Quinazolines, RNA Interference, Real-Time Polymerase Chain Reaction, B-Cell Antigen Receptors, RNA Sequence Analysis, Signal Transduction, TNF Receptor-Associated Factor 2, TNF Receptor-Associated Factor 3, Trypan Blue |
| Source: | Nature Medicine |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Volume: | 20 |
| Number: | 1 |
| Page Range: | 87-92 |
| Date: | January 2014 |
| Official Publication: | https://doi.org/10.1038/nm.3435 |
| PubMed: | View item in PubMed |
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