Targeting the Non-Canonical NF-κB Pathway in Chronic Lymphocytic Leukemia and Multiple Myeloma

Cancers

Georgia Broad¹  Iona Ashworth¹  Thomas A. Burley¹  Chris Pepper¹  Andrea G. S. Pepper¹  Emma Kennedy¹  Eleni E. Ladikou¹  Simon Mitchell¹  Rosalynd Johnston²  Melanie Boyd³  Christopher Fegan³  David Li³  Timothy Woo³  Simon P. Mackay⁴  Christopher West⁴ 

[1] Department of Clinical and Experimental Medicine, Brighton and Sussex Medical School, Falmer BN1 9PX, UK;Department of Haematology, Brighton and Sussex University Hospital Trust, Brighton BN2 5BE, UK;Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK;Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK;

关键词: NF-κB inducing kinase;    chronic lymphocytic leukemia;    multiple myeloma;    NF-κB;    synergy;   

DOI  :  10.3390/cancers14061489

来源: DOAJ

【 摘 要 】

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; r² = 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.

【 授权许可】

Unknown