Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 30 December 2021 / Approved: 31 December 2021 / Online: 31 December 2021 (12:23:29 CET)

A peer-reviewed article of this Preprint also exists.

Profitós-Pelejà, N.; Santos, J.C.; Marín-Niebla, A.; Roué, G.; Ribeiro, M.L. Regulation of B-Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas. Cancers 2022, 14, 860. Profitós-Pelejà, N.; Santos, J.C.; Marín-Niebla, A.; Roué, G.; Ribeiro, M.L. Regulation of B-Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas. Cancers 2022, 14, 860.

Journal reference: Cancers 2022, 14, 860
DOI: 10.3390/cancers14040860

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, 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 like 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.

Keywords

B-cell non-Hodgkin lymphoma (B-NHL); B-cell receptor (BCR); Bruton’s tyrosine kinase (BTK); spleen tyrosine kinase (SYK); phosphoinositide-3-kinase (PI3K); ibrutinib; acalabrutinib; copanlisib; idelalisib; umbralisib; fostamatinib; combination therapies

Subject

LIFE SCIENCES, Immunology

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