Rahal, Rami, Frick, Mareike, Romero, Rodrigo, Ruddy, David, Derti, Adnan, Rakiec, Daniel, Naylor, Tara, Kauffmann, Audrey, Pfister-Wagner, Estelle, Fritsch, Christine, Kovats, Steven, Kim, Sunkyu, Dietze, Kerstin, Dorket, Bernd, Tzankov, Alexandar, Hummel, Michael, Monahan, John, Morrissey, Michael, Sellers, William, Lenz, Georg, Cooke, Vesselina, Bhang, Hyo-Eun, Farsidjani, Alireza, Hernandez-Ilizaliturri, Francisco J, 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