Activation du récepteur des lymphocytes B : mécanismes moléculaires et cibles thérapeutiques.

The B cell receptor (BCR) is a membrane receptor specific to B cells and involved in the selection, activation, maturation, survival and proliferation of these cells. Its activation involves a large number of proteins, triggering a series of signalling pathways which, if they become constitutive, particularly via mutations, may be at the origin of and/or be key in many B cancers. The BCR associates with various co-receptors such as CD19, CD20 or CD22, thus positively or negatively regulating the signalling cascades induced by its activation. These include mitogen-activated protein kinases (MAPK), nuclear factor- κ B (NF- κ B), nuclear factor of activated T-cells (NF-AT) and protein kinase B (AKT); their activation is particularly dependent on BCR-related proteins such as Bruton's agammaglobulinemia tyrosine kinase (BTK) or phospho-inositide 3-kinase (PI3K). Targeting these proteins with inhibitors such as ibrutinib or idelasib has revolutionised the treatment of certain B cancers for which constitutive BCR hyperactivation could not, until now, be effectively attenuated. A great deal of research, both basic and clinical, is underway to identify other therapeutics that can specifically target (i) the different signalling pathways mentioned above, (ii) proteins directly linked to the BCR, or (iii) co-receptors associated with it. This review presents all existing therapies to date, innovative treatments currently in clinical trials and innovative treatments proposed by fundamental research. These include therapies using the most innovative technologies, such as conjugated monoclonal antibodies, chimeric antigen receptor T cells (CAR-T cells) and inhibitors capable of reversible covalent binding. In addition, this review accurately describes the therapeutic effects of alternative targets in the context of resistance to prolonged treatments. Such resistance, particularly to ibrutinib, represents a major public health issue and needs to be studied regularly in order to keep pace with the development of cancers in society. [ABSTRACT FROM AUTHOR]