Regulation of B-Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas
Profitós-Pelejà, Núria (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Santos, Juliana (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Marín-Niebla, Ana (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Roué, Gaël (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Ribeiro, Marcelo Lima (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)

Data:	2022
Resum:	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.
Ajuts:	Instituto de Salud Carlos III CD19/00228 Instituto de Salud Carlos III PI18/01383
Nota:	G.R. acknowledges supports from Fondo de Investigación Sanitaria PI18/01383, Spanish Ministry of Science and Innovation, European Regional Development Fund (ERDF) "Una manera de hacer Europa". J.C.S. holds a Sara Borrell research contract from Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (CD19/00228).
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	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 ; Combination therapies
Publicat a:	Cancers, Vol. 14 Núm. 4 (2-2 2022) , p. 860, ISSN 2072-6694

DOI: 10.3390/cancers14040860
PMID: 35205606

22 p, 1.0 MB

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