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

Mantle cell lymphoma (MCL) is an aggressive malignancy that is characterized by poor prognosis(1). 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-kappa B (NF-kappa B) pathway, whereas insensitive cell lines displayed activation of the alternative NF-kappa B pathway. Transcriptome sequencing revealed genetic lesions in alternative NF-kappa B 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-kappa B 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-kappa B or NIK-NF-kappa B pathways in MCL and provide critical insights into patient stratification strategies for NF-kappa B pathway-targeted agents.