Targeting the non-canonical NF-κB pathway in chronic lymphocytic leukemia and multiple myeloma

Burley, Thomas A. and Kennedy, Emma and Broad, Georgia and Boyd, Melanie and Li, David and Woo, Timothy and West, Christopher and Ladikou, Eleni E. and Ashworth, Iona and Fegan, Christopher and Johnston, Rosalynd and Mitchell, Simon and Mackay, Simon P. and Pepper, Andrea G. S. and Pepper, Chris (2022) Targeting the non-canonical NF-κB pathway in chronic lymphocytic leukemia and multiple myeloma. Cancers, 14 (6). 1489. ISSN 2072-6694 (

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In this study, we evaluated an NF-κB inducing kinase (NIK) inhibitor, CW15337, in primary chronic lymphocytic leukemia (CLL) cells, CLL and multiple myeloma (MM) cell lines and normal B-and T-lymphocytes. Basal NF-κB subunit activity was characterized using an enzyme linked immunosorbent assay (ELISA), and the effects of NIK inhibition were then assessed in terms of cytotoxicity and the expression of nuclear NF-κB subunits following monoculture and co-culture with CD40L-expressing fibroblasts, as a model of the lymphoid niche. CW15337 induced a dose-dependent increase in apoptosis, and nuclear expression of the non-canonical NF-κB subunit, p52, was correlated with sensitivity to CW15337 (p = 0.01; r 2 = 0.39). Co-culture on CD40L-expressing cells induced both canonical and non-canonical subunit expression in nuclear extracts, which promoted in vitro resistance against fludarabine and ABT-199 (venetoclax) but not CW15337. Furthermore, the combination of CW15337 with fludarabine or ABT-199 showed cytotoxic synergy. Mechanistically, CW15337 caused the selective inhibition of non-canonical NF-κB subunits and the transcriptional repression of BCL2L1, BCL2A1 and MCL1 gene transcription. Taken together, these data suggest that the NIK inhibitor, CW15337, exerts its effects via suppression of the non-canonical NF-κB signaling pathway, which reverses BCL2 family-mediated resistance in the context of CD40L stimulation.