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

Rahal, Rami and Frick, Mareike and Romero, Rodrigo and Ruddy, David and Derti, Adnan and Rakiec, Daniel and Naylor, Tara and Kauffmann, Audrey and Pfister-Wagner, Estelle and Fritsch, Christine and Kovats, Steven and Kim, Sunkyu and Dietze, Kerstin and Dorket, Bernd and Tzankov, Alexandar and Hummel, Michael and Monahan, John and Morrissey, Michael and Sellers, William and Lenz, Georg and Cooke, Vesselina and Bhang, Hyo-Eun and Farsidjani, Alireza and Hernandez-Ilizaliturri, Francisco J and Mavis, Cory and Stegmeier, Frank (2014) Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma. Nature Medicine, 20 (1). pp. 87-92. ISSN 1078-8956

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.

Item Type: Article
Date Deposited: 21 Nov 2017 00:45
Last Modified: 25 Jan 2019 00:46
URI: https://oak.novartis.com/id/eprint/9921

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