1. Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma
- Author
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Frank Stegmeier, Georg Lenz, Adnan Derti, Vesselina G. Cooke, Mareike Frick, Rami Rahal, Ali Farsidjani, Randy D. Gascoyne, Daniel P. Rakiec, Kerstin Dietze, Christine Fritsch, Robert Kridel, Michael Hummel, Tara L. Naylor, Barbara Meissner, Rodrigo Romero, Steve Kovats, Christian Steidl, Alexandar Tzankov, Joshua M. Korn, Dave Ruddy, Estelle Pfister, Fong Chun Chan, Audrey Kauffmann, William R. Sellers, Michael Morrissey, Bernd Dörken, Sunkyu Kim, John Monahan, and Hyo-eun C. Bhang
- Subjects
Cell Survival ,Ubiquitin-Protein Ligases ,B-cell receptor ,Blotting, Western ,Molecular Sequence Data ,Receptors, Antigen, B-Cell ,Lymphoma, Mantle-Cell ,Biology ,Protein Serine-Threonine Kinases ,Real-Time Polymerase Chain Reaction ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Inhibitor of Apoptosis Proteins ,chemistry.chemical_compound ,MAP3K14 ,Piperidines ,hemic and lymphatic diseases ,medicine ,Humans ,Pyrroles ,Protein kinase A ,DNA Primers ,Base Sequence ,TNF Receptor-Associated Factor 3 ,Sequence Analysis, RNA ,Adenine ,breakpoint cluster region ,NF-kappa B ,General Medicine ,Trypan Blue ,medicine.disease ,Microarray Analysis ,TNF Receptor-Associated Factor 2 ,Baculoviral IAP Repeat-Containing 3 Protein ,Lymphoma ,CARD Signaling Adaptor Proteins ,Pyrimidines ,chemistry ,Guanylate Cyclase ,Ibrutinib ,Luminescent Measurements ,Cancer research ,Quinazolines ,Pyrazoles ,Mantle cell lymphoma ,RNA Interference ,Signal transduction ,Signal Transduction - 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-κB (NF-κB) pathway, whereas insensitive cell lines displayed activation of the alternative NF-κB pathway. Transcriptome sequencing revealed genetic lesions in alternative NF-κB 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-κB 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-κB or NIK-NF-κB pathways in MCL and provide critical insights into patient stratification strategies for NF-κB pathway-targeted agents.
- Published
- 2013