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

Abstract

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.

Regulatory T cells (Tregs) in lymphoid malignancies and the impact of novel therapies

“…Targeted therapies have emerged as promising alternative treatments options to standard chemoimmunotherapy for B-NHL patients ( 102 ). Currently, approved targeted therapies include the immunomodulatory drug (iMiD) lenalidomide, several BTK inhibitors, BCL-2 inhibitor venetoclax, and several PI3K inhibitors ( 102 ).…”

“…Targeted therapies have emerged as promising alternative treatments options to standard chemoimmunotherapy for B-NHL patients ( 102 ). Currently, approved targeted therapies include the immunomodulatory drug (iMiD) lenalidomide, several BTK inhibitors, BCL-2 inhibitor venetoclax, and several PI3K inhibitors ( 102 ). Although these inhibitors primarily target malignant B cells, they can directly modulate other immune cells, including T cells, due to cellular homology and off-target activity ( 103 ).…”

“…Both BTK and ITK belong to the TEC family of kinases ( 117 ). While BTK is expressed in B cells and crucial for B-cell receptor signaling ( 102 ), ITK is expressed in T cells and necessary for control of TH differentiation ( 118 ), including Treg/Th17 balance ( 119 ). Accordingly, ibrutinib directly regulates T cells via ITK inhibition ( 120 ).…”

Integrated microRNA–mRNA Expression Profiling Identifies Novel Targets and Networks Associated with Autism

“…The ASD LCLs demonstrated upregulation of several oncogenes, including SYK [ 53 , 54 , 55 ], MFHAS1 [ 56 , 57 , 58 , 59 ], and TCL1A [ 60 ]. Interestingly, MFHAS1 has also been implicated in sepsis-associated encephalopathy [ 61 ] and intellectual impairment [ 62 ].…”

Targeting Protein Degradation Pathways in Tumors: Focusing on their Role in Hematological Malignancies

“…A novel approach with targeting proteins for degradation was applied for Bruton tyrosine kinase (BTK)-driven hematological malignancies. BTK is a vital part of the signaling pathway downstream from the B-cell receptor (BCR), and its continuous activation is a hallmark of several hematological malignancies [ 65 , 66 , 67 ]. Inhibitors of BTK became a promising therapeutic modality in the treatment of e.g., chronic lymphocytic leukemia (CLL), Waldenstrom macroglobulinemia (WM), and mantle cell lymphoma (MCL) [ 65 , 68 , 69 , 70 ].…”