DLBCL is the most common lymphoma with high tumor heterogeneity. Treatment refractoriness and relapse from R-CHOP therapy in patients remain a clinical problem. Activation of the non-canonical NF-κB pathway is associated with R-CHOP resistance. However, downstream targets of non-canonical NF-κB mediating R-CHOP-induced resistance remains uncharacterized. Here, we identify the common mechanisms underlying both intrinsic and acquired resistance that are induced by doxorubicin, the main cytotoxic component of R-CHOP. We performed global transcriptomic analysis of (1) a panel of resistant versus sensitive and (2) isogenic acquired doxorubicin-resistant DLBCL cell lines following short and chronic exposure to doxorubicin respectively. Doxorubicin-induced stress in resistant cells activates a distinct transcriptional signature that is enriched in metabolic reprogramming and oncogenic signalling. Selective and sustained activation of non-canonical NF-κB signalling in these resistant cells exacerbated their survival by augmenting glycolysis. In response to doxorubicin, p52-RelB complexes transcriptionally activated multiple glycolytic regulators with prognostic significance through increased recruitment at their gene promoters. Targeting p52-RelB and their targets in resistant cells increased doxorubicin sensitivity in vitro and in vivo. Collectively, our study uncovered novel molecular drivers of doxorubicin-induced resistance that are regulated by non-canonical NF-κB pathway. We reveal new avenues of therapeutic targeting for R-CHOP-treated refractory/relapsed DLBCL patients.
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The RNA-seq datasets generated during and/or analysed during the current study had been deposited in the GEO (Gene Expression Omnibus) database under the accession number GSE215900.
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We thank Hui Fen Kerry May Lim and Dachuan Huang from National Cancer Centre, Singapore for establishing the PDX model. This study is funded by the National Research Foundation (NRF) Singapore, under its Singapore NRF Fellowship (NRF-NRFF2018-04). In addition, we thank the Nanyang Assistant Professorship (NAP) Start-up-grant to Y.L. lab and National Medical Research Council (NMRC-OFLCG-18May0028), Tanoto Foundation and Ling Foundation for their support.
The authors declare no competing interests.
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Lim, S.K., Peng, C.C., Low, S. et al. Sustained activation of non-canonical NF-κB signalling drives glycolytic reprogramming in doxorubicin-resistant DLBCL. Leukemia 37, 441–452 (2023). https://doi.org/10.1038/s41375-022-01769-w