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Nat Med. 2014 Jan;20(1):87-92. doi: 10.1038/nm.3435. Epub 2013 Dec 22.

Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma.

Author information

1
1] Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA. [2].
2
1] Department of Hematology, Oncology and Tumor Immunology, Molecular Cancer Research Center, Charité-Universitätsmedizin, Berlin, Germany. [2].
3
Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
4
Department of Pathology and Experimental Therapeutics, BC Cancer Agency and BC Cancer Research Centre, Vancouver, British Columbia, Canada.
5
Novartis Institutes for Biomedical Research, Basel, Switzerland.
6
Department of Hematology, Oncology and Tumor Immunology, Molecular Cancer Research Center, Charité-Universitätsmedizin, Berlin, Germany.
7
Institute of Pathology, University Hospital Basel, Basel, Switzerland.
8
Department of Pathology, Charité-Universitätsmedizin, Berlin, Germany.

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.

PMID:
24362935
DOI:
10.1038/nm.3435
[Indexed for MEDLINE]

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