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

A screen for compounds that may inhibit the growth of hematological malignancies reveals the specific dependence of some mantle cell lymphoma (MCL) cell lines on canonical or alternative NF-κB signaling. As also seen in patients, genetic alterations affecting alternative NF-κB signaling confer insensibility to ibrutinib, a compound that was recently approved for MCL treatment. This alternative signaling pathway underscores the need to tailor treatments to the specific driving pathways in each patient group. 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-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.