Classical and alternative NF-κB pathway activation is mutually exclusive in mantle cell lymphoma.

  • Major finding: Classical and alternative NF-κB pathway activation are mutually exclusive in mantle cell lymphoma.

  • Concept: Alternative NF-κB pathway lesions confer dependence on NIK-mediated alternative NF-κB signaling.

  • Impact: Patients with alternative NF-κB pathway mutations are not likely to benefit from BCR pathway inhibitors.

Mantle cell lymphoma is a subtype of non-Hodgkin lymphoma with a poor prognosis. In a drug sensitivity screen, Rahal and colleagues noted that some mantle cell lymphoma cell lines were highly sensitive to the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and the protein kinase C (PKC) inhibitor sotrastaurin, although other mantle cell lymphoma cell lines were insensitive to both drugs. Given that BTK and PKC act downstream of the B-cell receptor (BCR) to activate the classical NF-κB pathway, the authors evaluated the effects of ibrutinib and sotrastaurin on NF-κB signaling and found that both agents specifically suppressed IκBα phosphorylation and downregulated NF-κB target genes in sensitive cell lines. Consistent with these findings suggesting dependence on BCR-dependent classical NF-κB signaling, ibrutinib- and sotrastaurin-sensitive cell lines were also sensitive to an inhibitor of IKKβ. However, IKKβ inhibition also reduced proliferation and downregulated NF-κB target genes in ibrutinib- and sotrastaurin-resistant mantle cell lymphoma cell lines, raising the possibility that these cell lines may be dependent on the alternative NF-κB pathway. Indeed, nuclear levels of the alternative NF-κB proteins p52 and RelB were specifically elevated in ibrutinib- and sotrastaurin-resistant cell lines, and knockdown or inhibition of NF-κB inducing kinase (NIK), which activates the alternative NF-κB pathway, blocked growth of ibrutinib- and sotrastaurin-resistant mantle cell lymphoma cells in vitro and in vivo. Sequencing of alternative NF-κB pathway genes in mantle cell lymphomas revealed that 15% of patients had mutations in either TRAF2 or BIRC3, which encode negative regulators of NIK, and patient-derived variants were impaired in their ability to inhibit NIK or block p52 accumulation. These findings indicate that a subset of patients with mantle cell lymphoma are unlikely to respond to inhibitors of BCR-dependent classical NF-κB signaling and instead may benefit from inhibitors of the alternative NF-κB pathway.

Rahal R, Frick M, Romero R, Korn JM, Kridel R, Chan FC, et al. Pharmacological and genomic profiling identifies NF-κB–targeted treatment strategies for mantle cell lymphoma. Nat Med 2014;20:87–92.

Note:Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.