Mantle cell lymphoma (MCL) is a rare form of B cell malignancy that is very difficult to treat. Some, but not all, patients respond to the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which inhibits signaling downstream of the B cell receptor. Protein kinase C β (PKCβ) couples the activation of BTK with that of the transcription factor nuclear factor κB (NF-κB). By analyzing various MCL cell lines, Rahal et al. found that noncanonical signaling through the NF-κB pathway determined the response of these cell lines to the combined effects of ibrutinib and the pan-PKC inhibitor sotrastaurin (STN). NF-κB activity was inhibited by STN in the MCL cell lines that showed reduced proliferation after ibrutinib/STN treatment, and the expression of NF-κB target genes was selectively inhibited by STN or ibrutinib only in the drug-sensitive cell lines. RNA sequencing and Western blotting analyses showed that TRAF2 and TRAF3, two of the components of a complex that targets the kinase NIK for degradation to suppress noncanonical NF-κB signaling, were absent in ibrutinib/STN-insensitive MCL cell lines. Indeed, five of the six ibrutinib/STN-insensitive MCL cell lines exhibited enhanced noncanonical NF-κB signaling, whereas all four of the ibrutinib/STN-sensitive cell lines did not. Knockdown or inhibition of the kinase NIK in ibrutinib/STN-insensitive MCL cell lines reduced their proliferation and the extent of noncanonical NF-κB signaling. In a mouse xenograft model, knockdown of NIK in an ibrutinib/STN-insensitive cell line reduced lymphoma growth and the expression of NF-κB target genes. Sequence analysis revealed mutations in genes encoding components of the noncanonical NF-κB signaling pathway in almost 10% of primary MCL samples. Together, these data suggest that aberrant noncanonical NF-κB signaling in MCL cell lines correlates with insensitivity to ibrutinib/STN and that NIK may be a potential therapeutic target in patients with ibrutinib-resistant MCL.
R. Rahal, M. Frick, R. Romero, J. M. Korn, R. Kridel, F. Chun Chan, B. Meissner, H.-e. Bhang, D. Ruddy, A. Kauffmann, A. Farsidjani, A. Derti, D. Rakiec, T. Naylor, E. Pfister, S. Kovats, S. Kim, K. Dietze, B. Dörken, C. Steidl, A. Tzankov, M. Hummel, J. Monahan, M. P. Morrissey, C. Fritsch, W. R. Sellers, V. G. Cooke, R. D. Gascoyne, G. Lenz, F. Stegmeier, Pharmacological and genomic profiling identifies NF-κB–targeted treatment strategies for mantle cell lymphoma. Nat. Med. 20, 87–92 (2014). [PubMed]