title: Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma.
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.
authors.affiliation: 1] Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA. [2].
authors.forename: Rami
authors.identifier: 0000000273139607
authors.initials: R
authors.lastname: Rahal
authors.affiliation: 1] Department of Hematology, Oncology and Tumor Immunology, Molecular Cancer Research Center, Charité-Universitätsmedizin, Berlin, Germany. [2].
authors.forename: Mareike
authors.initials: M
authors.lastname: Frick
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Romero
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Korn
authors.affiliation: Department of Pathology and Experimental Therapeutics, BC Cancer Agency and BC Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Kridel
authors.affiliation: Department of Pathology and Experimental Therapeutics, BC Cancer Agency and BC Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Fong Chun
authors.initials: FC
authors.lastname: Chan
authors.affiliation: Department of Pathology and Experimental Therapeutics, BC Cancer Agency and BC Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Barbara
authors.initials: B
authors.lastname: Meissner
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Hyo-eun
authors.initials: HE
authors.lastname: Bhang
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Dave
authors.initials: D
authors.lastname: Ruddy
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Audrey
authors.initials: A
authors.lastname: Kauffmann
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Farsidjani
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Adnan
authors.initials: A
authors.lastname: Derti
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rakiec
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Tara
authors.initials: T
authors.lastname: Naylor
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Estelle
authors.initials: E
authors.lastname: Pfister
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Kovats
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Sunkyu
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Molecular Cancer Research Center, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Dietze
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Molecular Cancer Research Center, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.affiliation: Department of Pathology and Experimental Therapeutics, BC Cancer Agency and BC Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: Department of Pathology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: John
authors.initials: J
authors.lastname: Monahan
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Morrissey
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Fritsch
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Vesselina G
authors.initials: VG
authors.lastname: Cooke
authors.affiliation: Department of Pathology and Experimental Therapeutics, BC Cancer Agency and BC Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.affiliation: 1] Department of Hematology, Oncology and Tumor Immunology, Molecular Cancer Research Center, Charité-Universitätsmedizin, Berlin, Germany. [2].
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
authors.affiliation: 1] Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA. [2].
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mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001483:Base Sequence; D015153:Blotting, Western; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D017931:DNA Primers / Q000235:genetics; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D010880:Piperidines; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000187:drug effects*; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism; D014343:Trypan Blue; D044767:Ubiquitin-Protein Ligases; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D000225:Adenine; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D053468:CARD Signaling Adaptor Proteins; D017931:DNA Primers; D006162:Guanylate Cyclase; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D010880:Piperidines; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D011743:Pyrimidines; D011758:Pyrroles; D011799:Quinazolines; D011947:Receptors, Antigen, B-Cell; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D014343:Trypan Blue; D044767:Ubiquitin-Protein Ligases; D000097782:NF-kappaB-Inducing Kinase; C090656:TRAF3 protein, human; C551803:ibrutinib; C543528:sotrastaurin; C494832:BIRC3 protein, human; C426242:CARD11 protein, human