Regulation of B-Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas

The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte's life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B-cell non-Hodgkin lymphomas (B-NHLs). In the last de...

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Published in:Cancers 2022-02, Vol.14 (4), p.860
Main Authors: Profitós-Pelejà, Núria, Santos, Juliana Carvalho, Marín-Niebla, Ana, Roué, Gaël, Ribeiro, Marcelo Lima
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Antigens
Apoptosis
B-cell lymphoma
B-cell receptor
Bruton's tyrosine kinase
Cell cycle
Disease
Drug delivery
Drug development
Immunoglobulins
Kinases
Lymphocytes B
Lymphoma
Mantle cell lymphoma
Medical prognosis
Mutation
Pathogenesis
Patients
Phosphatase
Phosphorylation
Physiology
Precision medicine
Protein-tyrosine kinase
Proteins
Review
Signal transduction
Spleen
Syk protein
Therapeutic targets
Toxicity
Transcription factors
Tumors
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Summary:The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte's life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B-cell non-Hodgkin lymphomas (B-NHLs). In the last decade, the emergence of BCR-associated kinases as rational therapeutic targets has led to the development and approval of several small molecule inhibitors targeting either Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (SYK), or phosphatidylinositol 3 kinase (PI3K), offering alternative treatment options to standard chemoimmunotherapy, and making some of these drugs valuable assets in the anti-lymphoma armamentarium. Despite their initial effectiveness, these precision medicine strategies are limited by primary resistance in aggressive B-cell lymphoma such as diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), especially in the case of first generation BTK inhibitors. In these patients, BCR-targeting drugs often fail to produce durable responses, and nearly all cases eventually progress with a dismal outcome, due to secondary resistance. This review will discuss our current understanding of the role of antigen-dependent and antigen-independent BCR signaling in DLBCL and MCL and will cover both approved inhibitors and investigational molecules being evaluated in early preclinical studies. We will discuss how the mechanisms of action of these molecules, and their off/on-target effects can influence their effectiveness and lead to toxicity, and how our actual knowledge supports the development of more specific inhibitors and new, rationally based, combination therapies, for the management of MCL and DLBCL patients.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers14040860