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CD79B limits response of diffuse large B cell lymphoma to ibrutinib
Joo Hyun Kim1, Won Seog Kim1,2, Kyungju Ryu1
1a Research Institute for Future Medicine, Samsung Medical Center , Sungkyunkwan University School of Medicine , Seoul , Korea ;
Abstract:
Blockage of B cell receptor signaling with ibrutinib presents a promising clinical approach for treatment of B-cell malignancies. However, many patients show primary resistance to the drug or develop secondary resistance. In the current study, cDNA microarray and Western blot analyses revealed CD79B upregulation in the activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL) that display differential resistance to ibrutinib. CD79B overexpression was sufficient to induce resistance to ibrutinib and enhanced AKT and MAPK activation, indicative of an alternative mechanism underlying resistance. Conversely, depletion of CD79B sensitized primary refractory cells to ibrutinib and led to reduced phosphorylation of AKT or MAPK. Combination of the AKT inhibitor or the MAPK inhibitor with ibrutinib resulted in circumvention of both primary and acquired resistance in ABC-DLBCL. Our data collectively indicate that CD79B overexpression leading to activation of AKT/MAPK is a potential mechanism underlying primary ibrutinib resistance in ABC-DLBCL, and support its utility as an effective biomarker to predict therapeutic response to ibrutinib.
Insights
CD79B upregulation causes ibrutinib resistance in activated B-cell like diffuse large B-cell lymphoma (ABC-DLBCL) by activating AKT and MAPK pathways. Targeting CD79B or these pathways can overcome resistance.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Ibrutinib is a promising treatment for B-cell malignancies by blocking B cell receptor signaling.
- Primary or secondary resistance limits ibrutinib's clinical efficacy in many patients.
- Activated B-cell like diffuse large B-cell lymphoma (ABC-DLBCL) exhibits variable responses to ibrutinib.
Purpose of the Study:
- To investigate the mechanisms of ibrutinib resistance in ABC-DLBCL.
- To identify potential biomarkers for predicting therapeutic response to ibrutinib.
- To explore combination therapies to overcome ibrutinib resistance.
Main Methods:
- cDNA microarray analysis to identify differentially expressed genes.
- Western blot analysis to assess protein expression and phosphorylation.
- Functional studies involving CD79B depletion and inhibition of AKT/MAPK pathways.
Main Results:
- CD79B was found to be upregulated in ibrutinib-resistant ABC-DLBCL.
- CD79B overexpression induced ibrutinib resistance and enhanced AKT/MAPK activation.
- CD79B depletion sensitized cells to ibrutinib and reduced AKT/MAPK phosphorylation.
- Combination therapy with AKT or MAPK inhibitors circumvented resistance.
Conclusions:
- CD79B overexpression activating AKT/MAPK is a key mechanism of ibrutinib resistance in ABC-DLBCL.
- CD79B serves as a potential biomarker for predicting ibrutinib treatment outcomes.
- Targeting CD79B or downstream signaling pathways offers a strategy to overcome ibrutinib resistance.
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