Pharmacological and Genomic Profiling Identifies NF-κB-targeted Treatment Strategies for Mantle Cell Lymphoma

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Baculoviral IAP Repeat-Containing 3 Protein
  • Base Sequence
  • Blotting, Western
  • CARD Signaling Adaptor Proteins / metabolism
  • Cell Line
  • Cell Survival
  • DNA Primers / genetics
  • Guanylate Cyclase / metabolism
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism
  • Luminescent Measurements
  • Lymphoma, Mantle-Cell / drug therapy*
  • Microarray Analysis
  • Molecular Sequence Data
  • NF-kappa B / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Pyrroles / pharmacology*
  • Quinazolines / pharmacology*
  • RNA Interference
  • Real-Time Polymerase Chain Reaction
  • Receptors, Antigen, B-Cell / antagonists & inhibitors
  • Receptors, Antigen, B-Cell / metabolism*
  • Sequence Analysis, RNA
  • Signal Transduction / drug effects*
  • TNF Receptor-Associated Factor 2 / genetics
  • TNF Receptor-Associated Factor 2 / metabolism
  • TNF Receptor-Associated Factor 3 / metabolism
  • Trypan Blue
  • Ubiquitin-Protein Ligases

Substances

  • CARD Signaling Adaptor Proteins
  • DNA Primers
  • Inhibitor of Apoptosis Proteins
  • NF-kappa B
  • PCI 32765
  • Pyrazoles
  • Pyrimidines
  • Pyrroles
  • Quinazolines
  • Receptors, Antigen, B-Cell
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 3
  • TRAF3 protein, human
  • sotrastaurin
  • BIRC3 protein, human
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Ubiquitin-Protein Ligases
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase
  • CARD11 protein, human
  • Guanylate Cyclase
  • Trypan Blue